Primary lipid Disorders

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Transcript Primary lipid Disorders

Disorders of lipid metabolism
Clinical manifestation of hyperlipidaemia:
Prolonged hyperlipidaemia results in
accumulation of lipid in tissues and causes cell
damage. Lipids may accumulate in arterial wall,
subcutaneous tissue, tendons and cornea
Subcutaneous tissue
The accumulation of lipids in subcutaneous tissue
causes xanthomatosis (xanthoma: is a yellow nodule
plaque). The nature of the lipid fraction most
affected usually determines the clinical appearance:
Eruptive xanthomata are crops of small, itchy,
yellow nodules (1-4mm) yellowish-brown papules.
They are associated with very high plasma VLDL or
chylomicron (triglyceride) concentrations, which
disappear if plasma lipid concentrations fall to
Appear over extensors of the elbows and knees, and on the
back and buttocks of patients with severe hyperlipidaemia
Disorders of lipid metabolism
Arterial walls.
-It is the most important
manifestation of lipid disorders.
-Cholesterol accumulation and
associated cellular proliferation
and fibrous tissue formation
produces atheromatous plaques.
-Atherosclerosis is due to
deformation and obstruction of the
artery that may result from
calcification and ulceration of
The small lipoproteins LDL and IDL
are atherogenic.
Soft yellow-orange plaques on the eyelids are lipid deposits under the
periorbital skin and may be associated with high plasma LDL-cholesterol
Tendinous Xanthomata and usually on Achilles tendons or the extensor tendons
of the hands occur in familial hypercholesterolaemia
Corneal arcus under the age of 40 may be
caused by the deposition of lipids and
associated with high plasma LDLcholesterol concentrations.
Classification of Disorders of lipid metabolism
Currently there is no satisfactory comprehensive classification of lipoprotein
In practice, lipoprotein disorders are classified as being:
Primary-when the disorder is not due to an identifiable underlying disease.
Secondary-when the disorder is a manifestation of some other disease.
Primary lipid Disorders:
Genetic classifications: are becoming increasingly complex as different
mutations are discovered Familial hypercholesterolaemia (FH), may be due
to any of over 500 different mutations of the LDL receptor gene.
*The same genotype can be expressed as more than one phenotype in
different individuals. i.e different clinical manifestations (signs and
symptoms) in different individuals for the same genetic disorder.
*These manifestations depend on the severity of the case, and on the life
*Until gene therapy and/or specific substitution therapy become more
available, genetic classifications, are unlikely to prove very useful in
Genetic classifications:
Genetic defect
Reduced number of
functional LDL receptors
IIa or IIb
Possibly single gene
IV or V
Familail combined
Possibly single gene
IIa, IIb, IV or V
Lipoprotein lipase
Reduced levels of
functional LPL
Apo C-II deficiency
Inability to synthesize apo
C-II (cofactor of LPL)
Inability to synthesize apo
Fat soluble vitamins
neurological deficit
Inability to synthesize apo
Neurological deficit,
CE storage in
abnormal places
WHO classification of dyslipidemia: based on Fredrickson work and it
is phenotypic classification based on the observation pattern of
lipoprotein abnormality
*The Fredrickson or World Health Organization classification is the
most widely accepted for the primary hyperlipidaemias.
* It is based the appearance of fasting plasma sample after
standing for 12 hr at 4°C and analysis of its cholesterol and TG
* As a result, patients with the same genetic defect may fall into
different groups, or may change grouping as the disease progresses or
* The major advantage of this classification is that it is widely accepted
and gives some guidance for treatment
*The six types by Fredrickson are not equally common. Type I and V are
rare, while types IIa, IIb and IV are very common.
Fredrickson (WHO) classification of dyslipidaemia
Fredrickson (WHO) classification of dyslipidaemia
Predominant hypercholesterolaemia
The risk of developing cardiovascular disease increases as the plasma cholesterol
concentration rises above 200 mg/dl in the absence of other risk factors this
value could be raised
Causes of hypercholesterolaemia
- Hypercholesterolaemia associated with little or no elevation of plasma
triglyceride concentration is almost always due to a raised plasma LDL
*The coexistence of an underlying genetic defect or other lipid disorders cause a
greater increase in plasma cholesterol with age.
Secondary hypercholesterolaemia.
Disorders that may produce a secondary increase in plasma total and LDLcholesterol
-primary hypothyroidism,
-diabetes mellitus,
-nephrotic syndrome,
-drugs (e.g.; thiazides).
Primary hyperlipidaemias
Familial hypercholesterolaemia (FH)
* This condition is characterized by high plasma cholesterol
concentrations which are present from early childhood and do not
depend upon the presence of environmental factors
* Different mutations can affect LDL synthesis, transport, ligand
binding, and recycling but all cause a similar phenotype.
*The familial incidence of hypercholesterolaemia, often associated with
an increased risk of ischemic heart disease, suggests an inherited
* Environmental and dietary factors may determine the expression of
the defect.
* The risk of developing cardiovascular disease is higher than normal,
compared with an age- and sex matched population.
Familial (monogenic) hypercholesterolaemia
Caused by a LDL receptor defect  reduced cellular uptake of LDL,
particularly by the liver  causes an increase in plasma total and LDLcholesterol concentrations.
Plasma triglyceride concentrations are either normal or only slightly
increased it is the most lethal of the inherited disorders.
In homozygotes LDL
receptors are virtually absent and plasma LDL-cholesterol is 3 to 4
times higher than those in normal subjects patients usually die before
the age of 20 from ischaemic heart disease.
In heterozygotes
The number of LDL receptors is reduced by 50% and the plasma
cholesterol concentrations are about twice those in normal subjects.
They have a 10 to 20-fold higher risk of developing ischaemic heart
disease than normal
Predominant hypertriglyceridaemia
* Elevated plasma triglyceride concentrations may be due to an increase in
plasma VLDL, or chylomicrons or both.
* Sustained and very high plasma concentrations of chylomicrons are
associated with abdominal pain and even acute pancreatitis, as well as
eruptive xanthomata.
* Many cases of hypertriglyceridaemia are symptom free. These large
lipoproteins are unlikely to cause artheroma, per se. However, many
patients with increased concentrations of VLDL-triglyceride have reduced
concentration of plasma HDL and increased plasma concentration of LDL or
IDL, which contain cholesterol.
* Hypertriglyceridaemia is usually secondary to another disease: obesity
and excessive carbohydrate intake, alcohol, drugs (thiazide diuretics) and
acute pancreatitis).
Familial endogenous hypertriglyceridaemia is caused by hepatic
triglyceride overproduction with increased VLDL secretion.
* The condition usually becomes apparent only after the fourth
* It may be associated with: obesity, glucose intolerance, decrease
in plasma HDL-cholesterol concentration and hyperuricaemia.
* Insulin resistance may be a common factor in the above conditions.
* High plasma triglyceride concentrations may cause eruptive
* primary hypertriglyceridaemia is less than primary
Familial combined hyperlipidaemia: Mixed hyperlipidaemia
 It is common disorder
 Associated with excessive hepatic production of apoB,  increase LDL
and VLDL-triglyceride synthesis due to either a primary or secondary
 Family members have a variety of different phenotypes.
 In one-third there is an increase in plasma LDL-cholesterol
 In another third there is an increase in both LDL-cholesterol and
 The remaining third have VLDL-hypertriglyceridaemia.
The lipid abnormalities appear significantly in the after the age 30
 The risk of ischaemic heart disease in all cases is higher
 Raised plasma concentrations of both cholesterol and triglycerides are
commonest in patients with poorly controlled diabetes mellitus, severe
hypothyroidism or the nephrotic syndrome.
* is usually due either to an acquired or inherited deficiency of
lipoprotein lipase.
* Insulin is needed for optimal enzyme activity  hyperchylomiconaemia
may occur in poorly controlled diabetic patients.
Inherited lipoprotein lipase deficiency may be due to:
A) True deficiency of the enzyme
B) Reduced activity of the enzyme because of apo C-II deficiency.
Which is an activator for lipoprotein lipase
-The plasma is very turbid because of the accumulation of chylomicrons.
-True lipoprotein lipase deficiency usually presents during childhood, with
signs and symptoms due to an excess of fat at skin, liver (hepatomegaly)
retinal vessels and abdomen.
- Hyperchylomiconaemia due to apoC-II deficiency is most likely to
present in adults.
Rare disorders associated with lipid metabolism
-A few rare disorders, which are associated with reduced plasma lipid concentration
but with the accumulation of lipid in tissues
- Inherited disorder of HDL deficiency (Tangier disease):
-Called also Analphalipoproteinaemia
-Associated with premature coronary heart disease.
-An abnormal apoA leads to an increased rate of catabolism of HDL.
-Plasma HDL concentrations are low and cholesterol esters accumulate in the
reticuloendothelial system.
Abetalipoproteinaemia (ApoB deficiency):
- absence of Apo B
- results in impaired synthesis of chylomicrons and VLDL, and therefore of LDL.
-lipids cannot be transported from the intestine to the liver.
- risk: decrease in fat soluble vitamins  lead to neurological defects, for treatment
vitamins are given I. V is given
In this condition there is partial deficiency of apo B; CM, VLDL and LDL are present,
but in low concentrations.
LCAT deficiency:
results in accumulation of free, mostly unesterified, cholesterol in tissues
Secondary lipid disorders
Secondary hyperlipoproteina is a well recognized feature of a number
of diseases
Common causes of secondary hyperlipidaemia including obesity and
diabetes mellitus.
Management should be directed towards the cause.
Effect of Alcohol on Lipid profile
Large quantity of Ethanol increases the synthesis of Fatty acid,
because of production of NADH and acetate
Fatty acid  TG  VLDL
Lipoprotein metabolism in diabetes mellitus
Insulin has a major role in the control of fat metabolism. Both type I and type 2
DM are associated with abnormalities of plasma lipids
In uncontrolled type I DM
* Marked hypertriglyceridaemia, increase in VLDL and often chylomicronaemia as a
result of decreased activity of lipoprotein lipase and increased activity of
hormone-sensitive lipase  leading to increased flux of free fatty acids from
adipose tissue  that act as a substrate for hepatic triglyceride synthesis
VLDL synthesis and accumulation  increase LDL.
* Both VLDL and chylomicrones need insulin for optimum catalysis.
The degree of hypertriglyceridaemia correlates well with glycaemic control and
insulin treatment can reverse the hypertriglyceidaemia.
* LDL can also be increased, and HDL is decreased.
*The VLDL contains increased triglyceride and cholesteryl ester in relation to the
amount of apolipoptotein
* Glycation of apolipoprotein B may enhance the atherogenicity of LDL by reducing
its affinity for the LDL receptor, so leading to increased uptake by macrophage
scavenger receptors.
* Treatment with lipid-lowering drugs may be appropriate, to reduce the risk of
vascular disease
Investigation of lipid disorders
Plasma sampling
• Plasma lipid concentrations and lipoprotein patterns are affected by
eating, smoking, alcohol intake, stress and changes in posture.
• It is essential that the samples are taken under standard conditions. The
following points are important:
1) Plasma cholesterol concentrations are not significantly affected after a
fatty meal while plasma triglyceride concentrations are affected.
Therefore, specimens for analysis of both should be taken after the
patient has fasted for 12 hours.
2) The patient should be taking a 'normal' diet and his weight should have
remained constant for about two weeks before the tests.
3) Unless treatment is being monitored, the patient must not be on any
drugs designed to lower plasma lipid concentrations
Investigation of lipid disorders
Plasma sampling
3) Unless treatment is being monitored, the patient must not be on any
drugs designed to lower plasma lipid concentrations
4) Lipoprotein concentrations, like those of all large particles, are
affected by venous stasis and posture. A standardized collection
procedure is important if serial estimations to assess the effect of
treatment are used.
5) Stress may affect plasma lipid concentrations like myocardial
infarction, major operation, or any serious illness.
6) The blood sample should not be heparinized and plasma or serum
must be separated from cells as soon as possible
Lipid profile
LDL-cholesterol is most commonly estimated from quantitative
measurements of total and HDL-cholesterol and plasma triglycerides (TG)
using the empirical relationship of Friedewald et al. (1972)
[LDL-chol] = [Total chol] - [HDL-chol] - ([TG]/5)
where all concentrations are given in mg/dL
The ([TG]/5) is used as an estimate of VLDL-cholesterol concentration. It
assumes, first, that virtually all of the plasma TG is carried on VLDL, and
second, that the TG:cholesterol ratio of VLDL is constant at about 5:1
(Friedewald et al. 1972).
Neither assumption is strictly true.
Limitations of the Friedewald equation:
The Friedewald equation should not be used under the following
When chylomicrons are present.
When plasma triglyceride concentration exceeds 400 mg/dL (4.52 mmol/L).
In circumstances in which these conditions apply, LDL-cholesterol should
be measured directly.
Reference ranges and laboratory investigation
Plasma conc at birth is very low (total chol less than 100 mg/dL 2.6 mmol/L) and
there is rapid increase in in first year of life
Elevated plasma chol is a major risk
factor for CHD
There are many CHD risk factors
Smoking will increase the risk factor
There is an inverse correlation between
HDL cholesterol and CHD risk.
So it is inappropriate to define a
reference range for plasma chol
But it is preferable to consider an
individual person's chol concentration
taking in consideration all other CHD risk
Coronary Heart Disease Risk Factors Determined By The NCEP
(National Cholesterol Education Program) and Adult Treatment
Positive Risk Factors
Age:  45 years for men;  55 years or premature menopause for women
Family history of premature CHD
Current cigarette smoking
Hypertension (BP  140/90 mmHg or taking antihypertensive medication)
LDL cholesterol concentration  160 mg/dL ( 4.1mmol/L), with ≤ 1 risk factor
LDL cholesterol concentration  130 mg/dL (3.4 mmol/L), with ≤ 2 risk factors
LDL cholesterol concentration  100 mg/dL (2.6 mmol/L), with CHD or risk
HDL cholesterol concentration < 40 mg/dL (< 1.0 mmol/L)
Diabetes mellitus = CHD risk equivalent
Negative Risk Factors
HDL cholesterol concentration  60 mg/dL ( 1.6 mmol/L)
LDL cholesterol < 100 mg/dL (2.6 < mmol/L)
Multiple metabolic risk factors
A diagnosis of metabolic
syndrome is made if a
patient has three or more of
the following:
Abdominal obesity (a waist
circumference of more than
40 inches [men] or 35 inches
2. An elevated triglyceride level
(150 mg/dL or higher)
3. A low HDL level (less than 40 mg/dL [men] or 50 mg/dL [women])
4. A high-normal or high blood pressure level (130/85 mm Hg or
5. A high fasting glucose level (110 mg/dL or higher)
Means 20 of 100
people with this level
of risk will have a
heart attack in the
next 10 years.
Risk Assessment Tool for Estimating Your 10-year Risk of
Having a Heart Attack
10-Year Risk Calculator
10-Year Risk Calculator Results
Risk Factor Intervention
• Target treatment based on risk
High: 10 year risk > 20%
Intermediate: 10 year risk 10 –20%
Low: 10 year risk < 10%
• Preventive strategies differ depending on risk category
Cholesterol lowering
Total cholesterol
Below 200
240 - 200
Aboveor 240
HDL cholesterol
Above 60
59 - 40
Below or 40
Below 150
499 - 150
Above or 500
LDL cholesterol
Below 130
160 - 130
Above or 160
The End
• Drugs: Thiaziade diuertics and b-blockers  hypertriglyceridaemia since these
drugs affect the homeostasis of K+ and Na+ which is important for the
conversion of proinsulin into insulin
low insulin levels  similar events of diabetes
• Hypothyrodism  low of T3, T4  decrease the uptake of LDL by the LDLreceptor mediated mechanism
• Nephrotic syndrome: increase the cholesterol level
NS is associated with loss of protein with the urine 
This will trigger the body to increase the synthesis of protein including Apo B
and other lipoproteins which lead to increase the cholesterol
Also may be due to loss of proteins responsible for regulation of lipid