PLASMA LIPIDS AND LIPOPROTEINS

Lipids play a critical role in almost all aspects of biological life – they are structural
components in cells and are involved in metabolic and hormonal pathways. The
importance of having a knowledge of lipid disorders cannot be overstated, not least
because they are common in clinical practice and, in some cases associated with
atherosclerosis such as coronary heart disease, one of the biggest killers in urbanized
societies.
Lipids are defined as organic compounds that are poorly soluble in water but
miscible in organic solvents.
Lipidology is the study of abnormal lipid metabolism.
An understanding of the pathophysiology of plasma lipid metabolism is usefully
based on the concept of lipoproteins, the form in which lipids circulate in plasma.

PLASMA LIPIDS
The chemical structures of the four main forms of lipid present in plasma are illustrated
in Figure 1

Figure 1:Lipid structure

Fatty acids are straight-chain carbon compounds of varying lengths. They may be
saturated, containing no double bonds, monounsaturated, with one double bond, or
polyunsaturated, with more than one double bond (Table 1).
Table 1:Some of the major fatty acids found in the plasma
Source
Group Name Carbon-chain length
Palmitoleic C16 Plant oil
Monounsaturated
Oleic C18 Olive oil
Linoleic C18 Plant oil
Linolenic C18 Plant oil
Polyunsaturated
Arachidonic C20 Plant oil
Eicosapentaenoic C20 Fish oil
Myristic C14 Coconut oil
Saturated Palmitic C16 Animal/plant oil
Stearic C18 Animal/plant oil

Fatty acids can esterify with glycerol to form triglycerides or be non-esterified

(NEFAs) or free. Plasma NEFAs liberated from adipose tissue by lipase activity are
transported to the liver and muscle mainly bound to albumin. The NEFAs provide
a significant proportion of the energy requirements of the body.

Triglycerides are transported from the intestine to various tissues, including the
liver and adipose tissue, as lipoproteins. Following hydrolysis, fatty acids are taken
up, re-esterified and stored as triglycerides. Plasma triglyceride concentrations rise after
a meal, unlike that of plasma cholesterol.

Phospholipids are complex lipids, similar in structure to triglycerides but containing

phosphate and a nitrogenous base in place of one of the fatty acids. They fulfill an
important structural role in cell membranes, and the phosphate group confers solubility
on non-polar lipids and cholesterol in lipoproteins.
Figure 2: Summary of fatty acid synthesis and adipose tissue substrates

Cholesterol is a steroid alcohol found exclusively in animals and present in

virtually all cells and body fluids. It is a precursor of numerous physiologically
important steroids, including bile acids and steroid hormones.. The rate-limiting
enzyme is 3-hydroxy3-methylglutaryl coenzyme A reductase (HMG-CoA reductase),
which is controlled by negative feedback by the intracellular concentration. About two-
thirds of the plasma cholesterol is esterified with fatty acids to form cholesterol esters.
LIPOPROTEINS
Because lipids are relatively insoluble in aqueous media, they are transported in
body fluids as, often spherical, soluble protein complexes called lipoproteins. Lipids
can be derived from food (exogenous) or synthesized in the body (endogenous). The
water-soluble (polar) groups of proteins, phospholipids and free cholesterol face
outwards and surround an inner insoluble (non-polar) core of triglyceride and
cholesterol esters.
Lipoproteins are classified by their buoyant density, which inversely reflects their
size. The greater the lipid to protein ratio, the larger their size and the lower the
density. Lipoproteins can be classified into five main groups . The first three are
triglyceride rich and, because of their large size, they scatter light, which can give
plasma a turbid appearance (lipaemic) if present in high concentrations:

• Chylomicrons are the largest and least dense lipoproteins and transport exogenous
lipid from the intestine to all cells.
• Very low-density lipoproteins (VLDLs) transport endogenous lipid from the liver to
cells.
• Intermediate-density lipoproteins (IDLs), which are transient and formed during the
conversion of VLDL to low-density lipoprotein (LDL), are not normally present in
plasma.
The other two lipoprotein classes contain mainly cholesterol and are smaller in size:
• Low-density lipoproteins(LDL) are formed from VLDLs and carry cholesterol to
cells.
• High-density lipoproteins (HDLs) are the most dense lipoproteins and are involved in
the transport of cholesterol from cells back to the liver (reverse cholesterol transport).
These lipoproteins can be further divided by density into HDL2 and HDL3.

Table 2:Characteristics of major lipoproteins

Lipoprotein Source Composition(%mass) Apolipoprotein Electrophoretic
Pro Cho Tg PL mobility
Chylomicrons Gut 1 4 90 5 A,B,C,E Origin

VLDL Liver 8 25 55 12 B,C,E Pre-β

LDL VLDL 20 55 5 20 B Β
via IDL
HDL Gut/ 50 20 5 25 A,C,E α
Liver
If a lipaemic plasma sample, for example after a meal, is left overnight at 4°C, the
larger and less dense chylomicrons form a creamy layer on the surface.
The smaller and denser VLDL and IDL particles do not rise, and the sample
may appear diffusely turbid. The LDL and HDL particles do not contribute to this
turbidity because they are small and do not scatter light. Fasting plasma from
normal individuals contains only VLDL, LDL and HDL particles.

In some cases of hyperlipidaemia, the lipoprotein patterns have been classified

according to their electrophoretic mobility (Fredrickson’s classification). Four principal
bands are formed, based on their relative positions, by protein electrophoresis, namely
α(HDL), pre-β(VLDL), β(LDL) and chylomicrons .
Intermediate-density lipoproteins in excess may produce a broad β-band. Some
individuals with hyperlipidaemia may show varying electrophoretic patterns at different
times.

Ultracentrifugation(separation based upon particle buoyant density) or

electrophoretic techniques are rarely used in routine clinical practice as these may
require completed apparatus and experienced operators. Instead, the lipoprotein
composition of plasma may be inferred from standard clinical laboratory lipid assays.
As fasting plasma does not normally contain chylomicrons, the triglyceride content
reflects VLDL. Furthermore, generally about 70 per cent of plasma cholesterol is
incorporated as LDL and 20 per cent as HDL. The latter particles, because of their high
density, can be quantified by precipitation techniques that can assay their cholesterol
content by subtraction, although direct HDL assays are now often used.
The Friedewald equation enables plasma LDL cholesterol concentration to be
calculated and is often used in clinical laboratories:

LDL cholesterol=total cholesterol – HDL cholesterol– [triglyceride]

2.2

This equation makes certain assumptions, namely that the patient is fasting and the
plasma triglyceride concentration does not exceed 4.5 mmol/L (otherwise
chylomicrons make the equation inaccurate).

There has been recent interest in the subdivision of LDL particles into small dense
LDL2 and LDL3 , which appear 2
to be more
3
atherogenic and more easily oxidized
than the larger LDL1 particles.
 Additionally, another lipoprotein called lipoprotein (a), or Lp(a), has been found.
This is similar in lipid composition to LDL but has a higher protein content. One
of its proteins, called apolipoprotein (a), shows homology to plasminogen and may
disrupt fibrinolysis, thus evoking a thrombotic tendency. The plasma concentration
of Lp(a) is normally less than 0.30 g/L and it is thought to be an independent
cardiovascular risk factor.
The proteins associated with lipoproteins are called apolipoproteins (apo). ApoA
(mainly apoA1 and apoA2 ) is the major group associated with HDL particles. 1 The apoB
2

series (apoB100 ) is predominantly found with LDL particles and is the ligand for the
LDL receptor. Low-density lipoprotein has one molecule of apoB 100 per particle. Some
reports have suggested that the plasma apoA 1 to apoB ratio may be a useful measure of
cardiovascular risk (increased if the ratio is less than 1) and it is not significantly
1
influenced by the fasting status of the patient. The apoC series is particularly important
in triglyceride metabolism and, with the apoE series, freely interchanges between
various lipoproteins. Some of the functions of these apolipoproteins are described in
Table 3.
Lipoprotein-associated phospholipase A2 [also called platelet-activating factor
acetylhydrolase (PAF-AH)] is present mainly on LDL and to a lesser degree HDL. It is
produced by inflammatory cells and is involved in atherosclerosis formation and levels
are associated with increased risk of coronary artery disease and stroke.
Table 3:The main apolipoproteins and their common functions
Apolipoprotein Associated lipoprotein Function
A1 Chylomicrons and HDL LCAT activator
A2 Chylomicrons and HDL LCAT activator
Secretion of
B48 Chylomicrons and VLDL
Chylomicrons/VLDL
B100 IDL.VLDL,LDL LDL receptor binding
Lipoprotein lipase
C2 Chylomicrons ,HDL, VLDL, IDL
activator
Lipoprotein lipase
C3 Chylomicrons ,HDL, VLDL, IDL
inhibitor
IDL and remnant particle
E Chylomicrons ,HDL, VLDL, IDL
receptor binding
Lipoprotein metabolism
Exogenous lipid pathways
Cholesterol and fatty acids released from dietary fats by digestion together with bile
are absorbed into intestinal mucosa cells where they are re-esterified to form
cholesterol esters and triglycerides. These together with phospholipids and apoA and
apoB are then secreted into the lymphatic system as chylomicrons. This secretion is
dependent upon apoB48 . The chylomicrons enter the systemic circulation via the
thoracic duct. Apolipoprotein C and apoE, both derived from HDL, are added to the
chylomicrons in the lymph and plasma.
The enzyme lipoprotein lipase is located on capillary walls and is activated by apoC 2
and inhibited by apoC 3 . It hydrolyses triglyceride to fatty acids and glycerol. The
former are taken up by adipose or muscle cells or bound to albumin in the plasma. The
glycerol component enters the hepatic glycolytic pathway. During their sojourn within
the circulation, the chylomicron particles get smaller and release some apoA and apoC
along with phospholipids, which then become incorporated into HDL particles. The
chylomicron remnants enriched in apoB and apoE and cholesterol then bind rapidly to
hepatic LDL-receptor-related protein, which recognizes the apoE ligand. Within the
hepatic cells the cholesterol is utilized and the apolipoproteins catabolized. Thus,
ultimately the exogenous pathway delivers triglyceride to adipose tissue and
muscle and cholesterol to the liver.

Endogenous lipid pathways (Fig. 6)

The liver is the main source of endogenous lipids. Triglycerides are synthesized from
fatty acids and glycerol, which may be derived from fat stores or glucose, respectively.
Hepatic cholesterol can either be derived from chylomicron remnants via the
exogenous pathway or synthesized locally. These lipids are transported from the
liver as VLDL.
Very low-density lipoprotein is a large triglyceride-rich particle consisting also of
apoB100 , apoC and apoE. Following hepatic secretion, it incorporates additional apoC
from HDL particles within the circulation.

Like chylomicrons, VLDL is hydrolysed by lipoprotein lipase in the peripheral

tissues, albeit more slowly. The resulting VLDL remnant or IDL contains cholesterol
and triglyceride as well as apoB and apoE and is rapidly taken up by the liver or
converted by the action of hepatic lipase to LDL by losing apoE and triglyceride.
Low-density lipoprotein is a small cholesterol-rich lipoprotein containing only apoB. It
represents about 70 per cent of the total plasma cholesterol concentration. It can be
taken up by most cells, although mainly the liver by the LDL or B/E receptor which
recognizes and binds apoB 100 . Within the cell, the LDL particles are broken down by
lysosomes, releasing cholesterol. This cholesterol can be incorporated into cell

Figure 6:Endogenous lipid pathways

membranes or in specific tissues such as the adrenal cortex or gonads and utilized in
steroid synthesis.
 Most
cells
are
able
to

synthesize cholesterol, but, to avoid intracellular accumulation, there is a feedback

control system reducing the rate of synthesis of the LDL receptors. Although most of
the plasma LDL is removed by LDL receptors, if the plasma cholesterol concentration
is excessive, LDL particles, by virtue of their small size, can infiltrate tissues by
passive diffusion and can even cause damage, as in atheroma formation within arterial
walls. An alternative route of removal of LDL is via the reticuloendothelial system,
collectively termed the scavenger cell pathway, which recognizes only chemically
modified LDL, for example oxidized LDL.
The liver has a central role in cholesterol metabolism:
• it contains most of the LDL receptors,
• it is responsible for most of the endogenous cholesterol synthesis,
• it takes up cholesterol from the diet via lipoproteins,
• it can excrete cholesterol from the body in bile.
Cholesterol is synthesized via a series of enzymatic steps, with HMG-CoA reductase
being the rate-limiting enzyme (Fig. 4). Suppression of this enzyme may occur if
cholesterol synthesis is excessive. Involved in these processes is a family of
transcription-regulating proteins called sterol regulatory element-binding proteins.
Intracellular cholesterol accumulation also reduces the number of hepatic LDL
receptors, and therefore LDL entry into cells declines and the plasma concentration
rises.
 .

Figure 7:LDL receptors

High-density lipoprotein
The transport of cholesterol from non-hepatic cells to the liver involves HDL
particles, in a process called reverse cholesterol transport (Fig. 8). The HDL is
synthesized in both hepatic and intestinal cells and secreted from them as small,
nascent HDL particles rich in free cholesterol, phospholipids, apoA and apoE.
This cholesterol acquisition is stimulated by adenosine triphosphate-binding
cassette protein 1 (ABC1). If the plasma concentration of VLDL or chylomicrons
is low, apoC is also carried in HDL, but as the plasma concentrations of these
lipoproteins rise, these particles take up apoC from HDL. In addition, HDL can
be formed from the surface coat of VLDL and chylomicrons. Various factors
control the rate of HDL synthesis, including oestrogens, thus explaining why
plasma concentrations are higher in menstruating women than in menopausal
women or men.
.
The HDL particles can be divided into pre- β(or precursor) HDL, HDL 2 and
HDL3 . The HDL2 , which is a precursor of smaller HDL 3 particles, interconverts
2
 as a result of the acquisition of cholesterol by HDL 3 through the actions of LCAT
and hepatic lipase.
High-density lipoprotein also contains other enzymes, including paroxanase,
which may have an antioxidant role. Removal of HDL may occur by endocytosis,
although there may be specific receptors such as the murine class B type I
scavenger receptor (SR-BI) in liver and steroidogenic tissue, for example adrenal
glands, ovaries and testes. Thus HDL-derived cholesterol can be ‘off-loaded’ in
the liver and secreted in bile or taken up and utilized for steroid synthesis.
High-density lipoprotein cholesterol is cardioprotective not only because of the
reverse cholesterol transport system, which helps to remove cholesterol from the
peripheral tissues, but also because of the mechanisms that include increased
atherosclerotic plaque stability, protection of LDL from oxidation, and
maintaining the integrity of the vascular endothelium.
A plasma HDL cholesterol concentration of less than 1.0 mmol/L confers
increased cardiovascular risk and can be raised by various lifestyle changes, such
as smoking cessation, regular exercise and weight loss.

.A low HDL cholesterol concentration is associated with diabetes mellitus type

2, obesity and the metabolic syndrome. Concentration of plasma non-HDL
cholesterol(total cholesterol–HDL cholesterol) may be a better indicator of
cardiovascular risk than that of LDL cholesterol.

LCAT: Lecithin–cholesterol acyltransferase is an enzyme that converts free cholesterol into cholesteryl ester.
DISORDERS OF LIPID METABOLISM
The study of hyperlipidaemias is of considerable importance, mainly because of
the involvement of lipids in cardiovascular disease.
Fredrickson, Levy and Lees first defined the hyperlipidaemias in a
classification system based on which plasma lipoprotein concentrations were
increased (Table).
Fredrickson’s classification hyperlipidaemias
Type Electrophoretic Increased lipoprotein
Chylomicrons
I Increased chylomicrons
ncreased β-lipoproteins
IIa LDL
Increased β and pre- β-lipoproteins
IIb LDL and VLDL
Broad β –lipoproteins
III IDL
Increased pre- β –lipoproteins
IV VLDL

Increased chylomicrons and pre- β -

V Chylomicrons and VLDL
lipoproteins

Although this so-called Fredrickson’s classification helped to put lipidology on

the clinical map, it was not a diagnostic classification. It gives little clue as to
the aetiology of the disorder; indeed, all of the phenotypes can be either primary
or secondary. Furthermore, the Fredrickson type can change as a result of dietary
or drug intervention. Nowadays, a more descriptive classification is used for the
primary hyperlipidaemias, as follows.
Chylomicron syndrome
This can be due to familial lipoprotein lipase deficiency, an autosomal
recessive disorder affecting about 1 in 1 000000 people. The gene for lipoprotein
lipase is found on chromosome 8, and genetic studies have shown insertions or
deletions within the gene.
Lipoprotein lipase is involved in the exogenous lipoprotein pathway by
hydrolysing chylomicrons to form chylomicron remnants, and also in the
endogenous pathway by converting VLDL to IDL particles.

Presentation as a child with abdominal pain (often with acute pancreatitis) is

typical. There is probably no increased risk of coronary artery disease. Gross
elevation of plasma triglycerides due to the accumulation of uncleared
chylomicron particles occurs .
Lipid stigmata include eruptive xanthomata, hepatosplenomegaly and
lipaemia retinalis .
Other variants of the chylomicron syndrome include circulating inhibitors of
lipoprotein lipase and deficiency of its physiological activator apoC 2 .
Apolipoprotein C2 deficiency is also inherited as an autosomal recessive
condition affecting about 1 in 1 000 000 people.
The gene for apoC2 is located on chromosome 19 and mutations resulting in
low plasma concentrations have been found.
Treatment of the chylomicron syndrome involves a low-fat diet.
In cases of apoC2 deficiency, fresh plasma may temporarily restore plasma
apoC2 levels. To confirm the diagnosis of familial lipoprotein lipase deficiency,

plasma lipoprotein lipase can be assayed after the intravenous

administration of heparin, which releases the enzyme from endothelial sites. The
assay is complicated in that other plasma lipases (hepatic lipase and
phospholipase, for example) contribute to the overall plasma lipase activity.
Inhibition of lipoprotein lipase can be performed using protamine, high saline
concentrations or specific antibodies and its overall activity can be calculated by
subtraction.
If apoC2 deficiency is suspected, the plasma concentrations of this activator
can be assayed. Patients may show a type I or type V Fredrickson’s phenotype.
Family members should be investigated.
Familial hypercholesterolaemia

This condition is characterized by high plasma cholesterol concentrations

that are present from early childhood and do not depend upon the presence of
environmental factors .
It is inherited as an autosomal dominant characteristic, with a prevalence in
the population in the UK of about 1 in 500. Different mutations can affect LDL
synthesis, transport, ligand binding, clustering in coated pits and recycling
but all cause a similar phenotype. Familial defective apo B-100, in which a
mutation in the apo B gene decreases the avidity of LDL for its receptor, causes
a similar phenotype. In all cases there is a defect in the uptake and catabolism of
LDL, and its plasma concentration is increased.

In heterozygotes, total cholesterol is typically in the range 7.5-12 mmol/L.

The diagnosis is based on the presence of hypercholesterolaemia (>7.5 mmol/L
in adults (LDLcholesterol >4.5 mmol/L)) together with tendon xanthomata in the
subject or tendon xanthomata or hypercholesterolaemia in a close relative.

In the very rare homozygotes (1 in 1,000,000), no receptors are present.

Plasma cholesterol concentrations can be as high as 20 mmol/L. These
individuals develop coronary artery disease in childhood and, if untreated, rarely
survive into adult life; heterozygotes tend to develop coronary artery disease
some 20 years earlier than the general population; more than half of those
untreated die before the age of 60.
Using Fredrickson’s classification, this condition has also been termed
familial type IIa hyperlipoproteinaemia, although some patients may show a
type IIb phenotype.
Familial defective apoB 3500
This condition is due to a mutation in the apoB gene resulting in a substitution
of arginine at the 3500 amino acid position for glutamine.
Apolipoprotein B is the ligand upon the LDL particle for the LDL receptor. It
may be indistinguishable clinically from FH and is also associated with
hypercholesterolaemia and premature coronary artery disease.
The treatment is similar to that for heterozygote FH. The apoB gene is
located upon chromosome 2.
Familial combined hyperlipidaemia
In familial combined hyperlipidaemia(FCH),the plasma lipids may elevated,
plasma cholesterol concentrations often being between 6 mmol/L and 9
mmol/L and plasma triglyceride between 2 mmol/L and 6 mmol/L.

The Fredrickson’s phenotypes seen in this condition include IIa, IIb and IV.
Familial combined hyperlipidaemia may be inherited as an autosomal dominant
trait (although others suggest that there may be co-segregation of more than one
gene).
About 0.5 per cent of the European population is affected, and there is an
increased incidence of coronary artery disease in family members. The metabolic
defect is unclear, although plasma apoB is often elevated due to increased
synthesis; LDL and VLDL apoB concentration is increased.
The synthesis of VLDL triglyceride is increased in FCH and there may also be
a relationship with insulin resistance.

The diagnosis of FCH is suspected if there is a family history of

hyperlipidaemia, particularly if family members show different lipoprotein
phenotypes. There is often a family history of cardiovascular disease.
However, the diagnosis can be difficult and it sometimes needs to be
distinguished from FH (xanthomata are not usually present in FCH) and
familial hypertriglyceridaemia (the IIa and IIb phenotypes are not usually
found in familial hypertriglyceridaemia, although they are in FCH).

Children with FCH usually show hypertriglyceridaemia and not the type IIa
phenotype (unlike the situation found in FH).
Unlike familial hypertriglyceridaemia, plasma VLDL particles are usually
smaller in FCH. Dietary measures and, if indicated, either a statin or a fibrate are
sometimes used.
Familial hypertriglyceridaemia
Familial hypertriglyceridaemia is often observed with low HDL cholesterol
concentration.
The condition usually develops after puberty and is rare in childhood. The
exact metabolic defect is unclear, although overproduction of VLDL or a
decrease in VLDL conversion to LDL is likely.
There may be an increased risk of cardiovascular disease. Acute pancreatitis
may also occur, and is more likely when the concentration of plasma
triglycerides is more than 10mmol/L.
Some patients show hyperinsulinaemia and insulin resistance.
Dietary measures, and sometimes lipid-lowering drugs such as the fibrates or
Omega-3 fatty acids, are used to treat the condition.

Type III hyperlipoproteinaemia

This condition is also called familial dysbeta-lipoproteinaemia or broad β-
hyperlipidaemia.
It is characterized clinically by the presence of fat deposits in the palmar
creases and by tuberous xanthomata; the latter tend to occur over bony
prominences and, unlike tendon xanthomata, are reddish in colour.

However, neither of these cutaneous stigmata is invariably present. In some

patients eruptive xanthomata are present.
Biochemically, the condition is characterized by the presence of an excess of
IDL and chylomicron remnants; chylomicrons are sometimes also present.
An alternative name is remnant hyperlipoproteinaemia.
Total cholesterol and triglyceride concentrations are elevated, typically to
approximately equal values.
This condition used to be called 'broad beta disease', because the remnant
particles give rise to a broad band extending between the pre-β (corresponding to
VLDL) and β (LDL) positions on serum lipoprotein electrophoresis. Patients
with remnant hyperlipoproteinaemia have an increased risk not only of coronary
artery disease but also of peripheral and cerebral vascular disease.

Apo E shows polymorphism. However, the fact that this phenotype is present
in l in 100 of the normal population, while dysbetalipoproteinaemia is an
uncommon disorder (prevalence approximately 1 in 10,000), implies a role for
other factors in its expression, and in this context it is noteworthy that although
the variant apoprotein is present from birth, the condition does not appear
clinically until adult life. Such factors include obesity, alcohol, hypothyroidism
and diabetes.
Although the diagnosis can be inferred from the clinical and biochemical
findings, it should ideally be confirmed by apo E genotyping.
Treatment consists of dietary measures, correcting the precipitating causes and
either the statin or fibrate drugs.
Polygenic hypercholesterolaemia
This is one of the most common causes of a raised plasma cholesterol
concentration.
This condition is the result of a complex interaction between multiple
environmental and genetic factors. In other words, it is not due to a single
gene abnormality, and it is likely that it is the result of more than one
metabolic defect.
There is usually either an increase in LDL production or a decrease in LDL
catabolism. The plasma lipid phenotype is usually either IIa or IIb Fredrickson’s
phenotype.
The plasma cholesterol concentration is usually either mildly or moderately
elevated. An important negative clinical finding is the absence of tendon
xanthomata, the presence of which would tend to rule out the diagnosis.
Usually less than 10 per cent of first-degree relations have similar lipid
abnormalities, compared with FH or FCH in which about 50 per cent of first-
degree family members are affected.
There may also be a family history of premature coronary artery disease.
Individuals may have a high intake of dietary fat and be overweight.
Treatment involves dietary intervention and sometimes the use of lipid-
lowering drugs such as the statins.

Hyperalphalipoproteinaemia
Hyperalphalipoproteinaemia results in elevated plasma HDL
cholesterol concentration and can be inherited as an autosomal dominant
condition or, in some cases, may show polygenic features.
The total plasma cholesterol concentration can be elevated, with normal LDL
cholesterol concentration. There is no increased prevalence of cardiovascular
disease in this condition; in fact, the contrary probably applies, with some
individuals showing longevity. Plasma HDL concentration is thought to be
cardioprotective, and individuals displaying this should be reassured.
Some causes of raised plasma high-density lipoprotein (HDL) cholesterol are
Primary
Hyperalphalipoproteinaemia
Cholesterol ester transfer protein deficiency
Secondary
High ethanol intake
Exercise
Certain drugs, e.g. estrogens, fibrates, nicotinic acid, statins, phenytoin,
rifampicin

Secondary hyperlipidaemias
One should not forget that there are many secondary causes of
hyperlipidaemia. These may present alone or sometimes parallel with a primary
hyperlipidaemia. Some of the causes of secondary hyperlipidaemia are listed
below:
Predominant hypercholesterolaemia
Hypothyroidism
Nephrotic syndrome
Cholestasis, e.g. primary biliary cirrhosis
Acute intermittent porphyria
Anorexia nervosa/bulimia
Certain drugs or toxins, e.g. ciclosporin and chlorinated hydrocarbons
Predominant hypertriglyceridaemia
Alcohol excess
Obesity
Diabetes mellitus and metabolic syndrome
Certain drugs, e.g. estrogens, β-blockers (without intrinsic sympathomimetic
activity), thiazide diuretics, acitretin, protease inhibitors, some neuroleptics and
glucocorticoids
Chronic kidney disease
Some glycogen storage diseases, e.g. von Gierke’s type I
Systemic lupus erythematosus
Paraproteinaemia

Other lipid abnormalities

Inherited disorders of low plasma HDL concentration
(hypoalphalipoproteinaemia) occur, and plasma HDL cholesterol concentration
should ideally be more than 1.0 mmol/L.
A number of such conditions have been described (such1 as apoA deficiency),
many of which are associated with premature cardiovascular disease.
 In Tangier’s disease, individuals have very low levels of HDL, large, yellow
tonsils, hepatomegaly and accumulation of cholesterol esters in the
reticuloendothelial system. There is a defect in the ABC1 gene involved in HDL
The causes of a low plasma HDL cholesterol are shown in the following
Primary
Familial hypoalphalipoproteinaemia
ApoA abnormalities
Tangier’s disease
Lecithin–cholesterolacyltransferase(LCAT) deficiency
Fish-eye disease
Secondary
Tobacco smoking
Obesity
Poorly controlled diabetes mellitus
Insulin resistance and metabolic syndrome
Chronic kidney disease
Certain drugs, e.g. testosterone, probucol, β-blockers (without intrinsic
sympathomimetic activity), progestogens, anabolic steroids, bexarotene

Defects of apoB metabolism have also been described.

In abetalipoproteinaemia or LDL deficiency there is impaired chylomicrons
and VLDL synthesis. This results in a failure of lipid transport from the liver and
intestine.
Transport of fat-soluble vitamins is impaired and steatorrhoea, progressive
ataxia, retinitis pigmentosa and acanthocytosis (abnormal erthyrocyte shape) can
result. In hypobetalipoproteinaemia, a less severe syndrome occurs, sometimes
due to a truncated form of apoB.

In LCAT deficiency, the accumulation of free unesterified cholesterol in

the tissues results in corneal opacities, renal damage, premature atherosclerosis
and haemolytic anaemia. The enzyme LCAT catalyses the esterification of free
cholesterol. Another condition that is probably due to a defect of LCAT is fish-
eye disease, in which there may be low HDL cholesterol concentrations and eye
abnormalities.
INVESTIGATION OF HYPERLIPIDAEMIAS
Before collecting blood, consider whether the patient is on lipid-lowering
therapy, including lipid-containing infusions. Also ensure that the patient fasts
overnight for around 12 h (if safe to do so) and is allowed only water to drink, if
required. Although plasma cholesterol concentration is little affected by fasting,
triglyceride concentrations rise and HDL cholesterol concentration decreases if
not, and thus ideally fasting samples should be requested. The patient should be
on his or her usual diet for a couple of weeks preceding the test.
Plasma lipids should not be assessed in patients who are acutely ill, for example
acute myocardial infarction,
Posture can alter plasma lipid concentrations: in the upright position, plasma
cholesterol concentration can be 10 per cent higher than in the recumbent
position.
The blood sample should be taken to the laboratory and assayed promptly. The
usual fasting lipid profile consists of plasma cholesterol, triglyceride and HDL
cholesterol concentrations.
Blood glucose concentration is useful to help assess for diabetes mellitus, liver
function tests for liver disease such as cholestasis, urinary protein and plasma
albumin concentrations for nephrotic syndrome and thyroid tests for
hypothyroidism.
It is generally wise to retest patient's lipid , a few months a part , as it is
recognized that within individual variation of lipid can be significant, and
reliance cannot be placed on just one set of readings.
Specialist lipid assays may help define the abnormality. The apoE genotype is
useful in the diagnosis of type III hyperlipoproteinaemia, . Plasma lipoprotein
lipase and apoC2 (its activator) assays may be useful in chylomicron syndrome,
and LDL receptor DNA studies for familial hypercholesterolaemia. Plasma
apoA1 and apoB concentrations and also Lp(a)may help define risk statu