DYSLIPIDEMIA: Prepared by

Darien Liew Daojuin

HYPERLIPOPROTEINEMIA 13 August 2017
INTRODUCTION
Dyslipidemia abnormal levels of lipids.
Hyperlipidemia is elevation of plasma cholesterol, triglycerides (TGs),
or both, or a low high-density lipoprotein level that contributes to the
development of atherosclerosis.

Dyslipidemias are disorders of lipoprotein metabolism that result in

the following abnormalities:
High total cholesterol (TC)
High low-density lipoprotein cholesterol (LDL-C)
High non-high-density lipoprotein cholesterol (non-HDL-C)
High triglycerides (TG)
Low high-density lipoprotein cholesterol (HDL-C)
NORMAL LIPID VALUES
PREVALENCE
The disturbance in lipoprotein metabolism is often familial.
54% of all patients with premature CHD (and 70% of those with a
lipid abnormality) had a familial disorder.

In the great majority of patients, inheritance is polygenic and the

expression of dyslipidemia is strongly influenced by factors such as
obesity (particularly central obesity) and the saturated fat and
cholesterol content of the diet.
The polygenic type of dyslipidemia is the major source of
atherosclerotic cardiovascular disease.
GENERAL OVERVIEW
Polygenic

Hypercholesterolemia Homozygous

Familial / Monogenic

Heterozygous

Acquired

Hypertriglyceridaemia Chylomicronemia

Hereditary
Hyperlipidemia
Familial
Hypertriglyceridemia

Familial dysbeta-
lipoproteinemia

Monogenic Familial combined

hyperlipedemia

Mixed

Polygenic Hyperapobeta-
lipoproteinemia
GENERAL OVERVIEW:
HYPERTRIGLYCERIDEMIA
Endrocrine Disorders

Pregnancy and
Hormones

Acquired

Hypercholesterolemia Renal Disorders

Hyperlipidemia Hypertriglyceridaemia Drugs

Mixed Chylomicronemia

Hereditary

Familial
Hypertriglyceridemia
CLASSIFICATION
BASED ON LIPIDS
FREDRICKSON CLASSIFICATION OF
HYPERLIPOPROTEINEMIA
 Average of
Elevated Serum Serum
Type overnight Associated clinical disorders
particles TC TG
serum

Creamy top Lipoprotein lipase deficiency, apolipoprotein C-II

I Chylomicrons N ++
layer deficiency

Familial hypercholesterolemia, polygenic

IIa Clear LDL hypercholesterolemia, nephrosis, hypothyroidism, ++ N
familial combined hyperlipidemia

IIb Clear LDL, VLDL Familial combined hyperlipidemia ++ +

III Turbid IDL Dysbetalipoproteinemia + +

Familial hypertriglyceridemia, familial combined

IV Turbid VLDL hyperlipidemia, sporadic hypertriglyceridemia, N+ ++
diabetes

Creamy top,
Chylomicrons,
V turbid Diabetes + ++
VLDL
bottom
HYPERCHOLESTEROLEMIA
Familial Hypercholesterolemia due to
1. LDL receptor defect
2. Defective Apo B100
3. Increased function of PCSK9
 Polygenic

Hypercholesterolemia

Familial / Monogenic

Hyperlipidemia Acquired

Hypertriglyceridaemia

Hereditary

Mixed
 It is a
FAMILIAL HYPERCHOLESTEROLEMIA disorder of
lipoprotein,
INTRODUCTION NOT LIPIDS.

Familial hypercholesterolemia (FH) is a genetic disease caused by

functional mutations at one of three genetic loci.

FH is the most common autosomal dominant genetic disease. The clinical syndrome
(phenotype) is characterized by extremely elevated levels of low density
lipoprotein cholesterol (LDL-C) and a propensity to early onset atherosclerotic
cardiovascular disease. Homozygotes generally manifest disease in childhood.
DYSLIPOPROTEINEMIA
It is a more preferred term over dyslipidemia because dyslipidemia
basically means a disorder in any form of the lipid metabolism, whilst
dyslipoproteinemia concerns more on the lipoprotein.

Since FH is largely due to a disorder in the LDL receptors and a high

amount of LDL in the blood, hence dyslipoproteinemia is preferred.
FAMILIAL HYPERCHOLESTEROLEMIA
GENETIC LOCI
Increased uptake of
modified LDL (oxidized or
Estimated that about 95% of patients with FH carry a other modifications) by
functional mutation of one of three genes the macrophage
scavenger receptors,
resulting in macrophage
lipid accumulation and
Mutation Consequence foam cell formation

The low density lipoprotein reduced clearance of LDL

receptor (LDLR or apoB/E) particles from the circulation and
an elevation in plasma LDL-C
Gain-of-function mutations of the leading to decreased LDL
proprotein convertase subtilisin metabolism
kexin 9 gene (PCSK9),
Apolipoprotein B gene (APOB), which impairs binding of LDL
particles to the LDL receptor
FAMILIAL HYPERCHOLESTEROLEMIA
LDLR DEFECT HOMOZYGOTE VS HETEROZYGOTES
FH is inherited with a gene dosing effect, in which homozygotes are
more adversely affected than heterozygotes.
FAMILIAL HYPERCHOLESTEROLEMIA
LDLR DEFECT HOMOZYGOTE VS HETEROZYGOTES

Homozygous FH is rare (1 in 1,000,000 births).

Heterozygous FH affects approximately 1 in 200 to 500 people in
North America and Europe. Patients have high LDL-C levels from birth,
premature CHD, a family history of hypercholesterolemia, and tendon
xanthomata. (Use the Dutch Lipid Clinic Network criteria)
FAMILIAL HYPERCHOLESTEROLEMIA
LDL RECEPTOR GENETIC DEFECTS

In its most common form, FH is a monogenic disorder caused by

defects in the gene that encodes for the apo B/E (LDL) receptor.
Results in reduced clearance of LDL particles from the circulation and an elevation in
plasma LDL-C.

There are more than 1600 different mutations in the LDLR gene. The mutations
at the LDLR locus have been categorized into four classes of alleles based on the
phenotypic behavior of the mutant protein:
Class I Null, in which synthesis is defective.
Class II Transport defective, in which intracellular transport from the
endoplasmic reticulum to Golgi is impaired.
Class III Binding defective, in which proteins are synthesized and
transported to the cell surface normally, but binding of LDL is defective.
Class IV Internalization defective, in which proteins reach the cell surface
and bind LDL normally but the receptors do not cluster in the coated pits,
thereby minimizing LDL internalization.
FAMILIAL HYPERCHOLESTEROLEMIA
MUTATIONS IN PCSK9 GENE
PCSK9 is a serine protease that is secreted by the liver into the plasma that
binds to an extracellular domain of the LDLR (principally) on liver cells. This
binding prevents LDL receptors from recycling to the cell surface and
ultimately accelerates their destruction inside liver cells.

In FH, there is an Prolonged

Oxidised LDL
increased in PCSK9, hyperlipidemia can
stimulates
cause endothelial injury,
this reduces the LDL inflammation.
LDL accumulates and get
receptors and oxidised by free
increases the LDL in The result is
radicals from
the blood. Atherosclerosis
macrophages.
FAMILIAL HYPERCHOLESTEROLEMIA
DEFECTIVE APO B100
Familial defective apo B-100 is an autosomal dominant disorder that,
like FH, is associated with impaired binding of LDL particles to the
apo B/E (LDL) receptor.

The net effect is that the clearance of LDL is reduced and plasma
levels increase by two- to threefold.
FAMILIAL HYPERCHOLESTEROLEMIA
DIAGNOSIS (1)

Mostly clinical, rarely genetic testing is considered.

American Heart Association criteria for the clinical diagnosis of FH:

low density lipoprotein cholesterol (LDL-C) >190 mg/dL (>4.9 mmol/l)

and either

a first degree relative with LDL-C>190 mg/dL or

with known premature coronary heart disease (<55 years men; <60 years women)
FAMILIAL HYPERCHOLESTEROLEMIA
DIAGNOSIS (2)
FAMILIAL HYPERCHOLESTEROLEMIA
DIAGNOSIS (3)
Polygenic Hypercholesterolemia

Polygenic

Hypercholesterolemia

Familial / Monogenic

Hyperlipidemia Acquired

Hypertriglyceridaemia

Hereditary

Mixed
POLYGENIC HYPERCHOLESTEROLEMIA
We can only differentiate this from the familial type via genetic
testing. Similar to patients with monogenic FH, these patients have
familial aggregation of moderate hypercholesterolemia and the
premature onset of coronary heart disease (CHD).
Poorly understood but multiple abnormalities in LDL metabolism are
likely involved.
These abnormalities in LDL metabolism include mild defects in the LDL
receptor, defective apo B-100, increased synthesis of apo B, and the
presence of the apo E4 phenotype.
Apo E is required for receptor-mediated clearance of chylomicron
and VLDL remnants from the circulation.
Impaired ApoE
clearance of
chylomicron
remnant and VLDL
Polygenic
Hypercholesterolemia
POLYGENIC HYPERCHOLESTEROLEMIA
ABOUT APO E
Ligand for hepatic chylomicron and VLDL remnant receptor, leading to
clearance of these lipoproteins from the circulation; ligand for LDL
receptor.
There are three different apo E alleles in humans:
E2, which has cysteine residues at positions 112 and 158
E3, which occurs in 60 to 80 percent of Caucasians and has cysteine at position 112 and
arginine at position 158
E4, which has arginine residues at positions 112 and 158.

These alleles encode for a combination of apo E isoforms that are

inherited in a codominant fashion.
Compared to apo E3, apo E2 has reduced affinity and apo E4 has
enhanced affinity for the LDL (apo B/E) receptor. These isoforms are
important clinically because apo E2 is associated with familial
dysbetalipoproteinemia (due to less efficient clearance of VLDL and
chylomicrons) and apo E4 is associated with an increased risk of
hypercholesterolemia and coronary heart disease.
 Mixed Hyperlipidemia

Polygenic

Hypercholesterolemia

Familial / Monogenic

Hypertriglyceridaemia

Familial dysbeta-
Hyperlipidemia
lipoproteinemia

Familial combined
Monogenic
hyperlipedemia

Mixed

Hyperapobeta-
Polygenic
lipoproteinemia
FAMILIAL COMBINED HYPERLIPIDEMIA
FCHL is thought to be a genetically complex disease and the
phenotype is usually determined by interaction of multiple
susceptibility genes and the environment.
Co-inheritance of two or more gene variants potentially affecting
lipoprotein metabolism are generally required for the expression of
FCHL.
In an autosomal dominant pattern, an overproduction of hepatically-
derived apo B-100 is associated with very low density lipoprotein
(VLDL).
FAMILIAL COMBINED HYPERLIPIDEMIA
FCHL can be represented by one of three Fredrickson phenotypes
Combined elevations of triglycerides and cholesterol resulting from increases
in VLDL and LDL (type IIb)
Hypercholesterolemia due to an increase in LDL (type IIa)
Isolated hypertriglyceridemia induced by a rise in VLDL (type IV)
HYPERAPOBELATALIPOPROTEINEMIA
Hyperapobetalipoproteinemia is characterized by an overproduction
of apo B and may be a variant of familial combined hyperlipidemia.
This condition is characterized by LDL that are enriched in apo B-100.
It is manifested clinically by an elevation in the concentration of apo B,
but a normal concentration of LDL-cholesterol (LDL-C).
In most cases, the LDL-C level is less than 160 mg/dL (4.1 mmol/L), the
LDL apo B concentration is greater than 135 mg/dL (3.5 mmol/L), and
the LDL-to-apo B ratio is less than 1.2 (normal value >1.4)
 Hypertriglyceridemia

Polygenic

Hypercholesterolemia

Familial / Monogenic

Acquired

Hyperlipidemia Hypertriglyceridaemia Chylomicronemia

Hereditary

Familial
Hypertriglyceridemia

Monogenic

Mixed

Polygenic
HYPERTRIGLYCERIDEMIA
The chylomicronemia syndrome is a disorder
characterized by severe hypertriglyceridemia
and massive accumulation of chylomicrons in
plasma.

Familial hypertriglyceridemia (type IV

hyperlipoproteinemia phenotype) is an autosomal
dominant disorder associated with moderate
elevations in the serum triglyceride concentration (200
to 500 mg/dL [2.3 to 5.6 mmol/L]).

It is often accompanied by insulin resistance, obesity,

hyperglycemia, hypertension, and hyperuricemia.
Patients with familial hypertriglyceridemia are
heterozygous for inactivating mutations of the LPL
gene and, as noted above, typically have low serum
HDL-C (hypoalphalipoproteinemia)
 Impaired ApoE
clearance of
chylomicron
Mutations in LPL, remnant and VLDL
Results in increased TG Polygenic
Hypercholesterolemia
Familial hyperTG
Chyclomicronemia
Overproduction of
hepatic Apo B100

Familial Combined
Hyperlipidemia
Hyperapobetaliproteinemia
Impaired LDL binding to LDLR
Increased plasma LDL

Familial
Hypercholesterolemia
LDLR defect
Dysfunctional PCSK9
Increased Apo B100
Secondary Causes: Hypertriglyceridemia

Endrocrine Disorders

Pregnancy and
Hormones

Acquired

Hypercholesterolemia Renal Disorders

Hyperlipidemia Hypertriglyceridaemia Drugs

Mixed Chylomicronemia

Hereditary

Familial
Hypertriglyceridemia
SECONDARY CAUSES: HYPERTRIGLYCERIDEMIA
ENDOCRINE: DIABETES

Insulin resistance and the ensuing hyperinsulinemia are associated with

hypertriglyceridemia and low serum HDL cholesterol concentrations.

Insulin resistance

Low glucose in cells,

no energy Hypocatabolism of
chylomicrons
Increase VLDL to cells
Endogenous Hepatic
Hypertriglyceridemia
Lipogenesis
Release of TG
Enhanced lipolysis
TG breakdown to produce from adipose tissue
energy
SECONDARY CAUSES: HYPERTRIGLYCERIDEMIA
ENDOCRINE: HYPOTHYROIDISM

Many hypothyroid patients have high serum concentrations of total

cholesterol and LDL cholesterol, and some have high serum
concentrations of TG, IDL, apoprotein A-1.

The increased risk of coronary artery disease seen in hypothyroid

patients is likely multifactorial in etiology.

The primary mechanism for hypercholesterolemia in hypothyroidism is

accumulation of LDL cholesterol due to a reduction in the number of
cell surface receptors for LDL, resulting in decreased catabolism of
LDL. Hence, increases circulatory LDL that is subject to oxidation and
atherosclerosis formation.
SECONDARY CAUSES: HYPERTRIGLYCERIDEMIA
ALCOHOL
Moderate alcohol consumption generally has favorable effects on
lipids probably due to its effect on CETP (CETP facilitates the
exchange of neutral lipids, particularly cholesteryl esters but also
triglycerides and to some degree phospholipids, from HDL to
triglyceride-enriched lipoproteins in exchange for triglyceride).

TG
HDL/ Cholesterol VLDL/
Phospholipids
LDL Estyl chylomicrons

Low CETP activity will reduce the redistribution of cholesterol from

HDL, thereby increasing serum HDL cholesterol concentrations.
Excessive alcohol consumption can raise triglyceride levels.
Probably causes some form of metabolic instability.
SECONDARY CAUSES: HYPERTRIGLYCERIDEMIA
NEPHROTIC SYNDROME

Marked elevations in the plasma levels of cholesterol, LDL,

triglycerides and lipoprotein(a) often occur. Total HDL cholesterol
levels are usually normal or reduced in the nephrotic syndrome.

The triggering factor is the reduction in plasma oncotic pressure, this

stimulates hepatic apo B gene transcription.

This causes both hypercholestrolemia and hypertriglyceridemia.

SECONDARY CAUSES: HYPERTRIGLYCERIDEMIA
DRUGS

Some drugs that lead to hypercholesterolemia include

Antipsychotic drugs
Clozapine
Olanzapine
Antiretroviral regimen
Protease inhibitors HIV associated lipodystrophy?
SECONDARY CAUSES: HYPERTRIGLYCERIDEMIA
HORMONES

Oral estrogen has a proven beneficial effect on serum lipid

concentrations, which can be negated in part by progestin therapy.
One study, for example, randomly assigned women to treatment with
0.625 mg of conjugated equine estrogens or placebo.
Estrogen had the following effects on mean serum lipid concentrations:
Low-density lipoprotein (LDL) cholesterol fell by 15%
High-density lipoprotein (HDL) cholesterol increased by 16%
Triglycerides increased by 24%
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Medscape
http://www.medscape.com/viewarticle/584885_3

NCBI
https://www.ncbi.nlm.nih.gov/pubmed/11905095

Robbins Basic Pathology, 9th Edition