Familial hypercholesterolaemia

What is cholesterol?
Cholesterol is one of the body's lipids. It is
one of the important building blocks in the
structure of cells and also is used in
production of hormones and energy.
The level of cholesterol in blood depends on
what you eat but it is mainly depends on how
cholesterol is produced by body.
"New Releases." Understanding Cholesterol: The Good, the Bad, and the Necessary. Web. 7 Dec. 2014.
<http://www.health.harvard.edu/newsweek/Understanding_Cholesterol.htm>.

Cholesterol is the biosynthetic precursor to a large
number of important steroids:
Cholesterol is
the precursor
to vitamin D.
7-Dehydrocholesterol Vitamin D3
Cholic Acid
Sodium Taurocholate
Bile Acids Vitamin D
Corticosteroids
Cortisol Cortisone
Testosterone
Sex Hormones
Estradiol Progesterone

LIPOPROTEIN
5 broad categories on the basis of their functional &
physical properties, primarily on their DENSITIES:
1. Chylomicrons
2. VLDL — very low density lipoprotein
3. IDL — intermediate density lipoprotein
4. LDL — low density lipoprotein
5. HDL — high density lipoprotein

What is Familial Hypercholesterolemia?
• The most common dominantly inherited disorder
• LDL cholesterol levels are highly elevated from birth
• FH is most caused in result of mutations in genes affecting the LDL receptor
that clears LDL particles from plasma
• FH accelerates atherosclerotic cardiovascular disease, especially coronary
heart disease
• Clinical manifestations often occurring after one to four decades of life
• More than 20 million people probably suffer from FH worldwide
"Familial Hypercholesterolemia ." Familial Hypercholesterolemia. Web. 7 Dec. 2014.
<http://emedicine.medscape.com/article/121298-overview#showall>.

Symptoms
 Xanthelasma
 Corneal arcus (Arcus senilis)
 Achilles tendon xanthomas
 Tendon xanthomas
 Tuberous xanthomas
 Palmar xanthomas
Heterozygous Familial
Hypercholesterolemia (HeFH)
 Monogenic disorder
 Heterozygous mutations in the LDLR
gene
 Cholesterol deposits in the corneas,
eyelids and extensor tendons
 Elevated plasma concentrations of LDL
Physical symptoms:

FH is almost always autosomal dominant FH is very rarely autosomal recessive
• Most common FH-causing mutations are in the LDL receptor
gene (LDLR).
• Less common defects include mutations in APOB or PCSK9
genes.
• Heterozygotes inherit a single abnormal gene from one parent,
Given the dominant mode of inheritance, these individuals
manifest the disorder.
• Heterozygotes have approximately 2- to 3-fold higher serum
LDL- cholesterol levels than normal.
• Homozygotes inherit an abnormal gene from both parents. They
typically have an LDL cholesterol level 3- to 6-fold higher than
normal .
• Mutations in the LDLRAP1 gene result in a very rare autosomal
recessive form of homozygous FH called autosomal recessive
hypercholesterolemia (ARH).
• The clinical phenotype of homozygous ARH is similar to classic
phenotypes.
• homozygous familial hypercholesterolemia but it is some what
milder in terms of serum total cholesterol and LDL-C levels .
• As it is a recessive disorder, most ARH patients are homozygous for
the same allele inherited from consanguineous or related parents.
• As ARH is an autosomal recessive disorder, the heterozygotes are not
affected

Genetics of FH
The most common genetic defects in FH are:
• LDLR mutations
• ApoB mutations
• PCSK9 mutations
• LDLRAP1.

"Chapter 3." Missense Mutation in the LDLR Gene: A Wide Spectrum in the Severity of Familial Hypercholesterolemia. Web. 5 Dec. 2014. <http://www.intechopen.com/books/mutations-in-human-
genetic-disease/missense-mutation-in-the-ldlr-gene-a-wide-spectrum-in-the-severity-of-familial-hypercholesterolemia>.

LDL receptor
 The LDLR gene provides the instructions
for making a protein called low-density
lipoprotein receptor.
 This receptor binds to particles called low-
density lipoproteins (LDLs), which are the
primary cholesterol cariers in the blood.
 The receptor is needed to remove LDL
from the bloodstream.

There are five major classes of FH due to
LDLR mutations:
 Class I: LDLR is not synthesized at all.
 Class II: LDLR is not properly transported .
 Class III: LDLR does not properly bind LDL on the
cell surface
 Class IV: LDLR bound to LDL does not properly
cluster in clathrin-coated pits for receptor-mediated
endocytosis.
 Class V: LDLR is not recycled

LDLR Mutation
number of low-density
lipoprotein receptors
produced within cells
are reduced.
High level of
blood
cholesterol
cholesterol deposited
abnormally in tissues such
as the skin, tendons, and
arteries
HYPERCHOLESTROLEMIA
"Hypercholesterolemia." Genetics Home Reference. Web. 5 Dec. 2014.
<http://ghr.nlm.nih.gov/condition/hypercholesterolemia#genes>.

Apolipoprotein B
 Five mutations in the APOB gene are known to
cause a hypercholesterolemia called familial
defective apolipoprotein B-100 (FDB).
 Each of these mutations changes a single protein
building block (amino acid) in a critical region of
apolipoprotein B-100.
Apo B (site where
receptor binds to LDL
particle)
LDL receptor
Cytosol
Cell membrane
Extracellular Fluid
PCSK9
LDL Particle:

ABOP mutation
a single protein
building block
(amino acid) in a
critical region of
apolipoprotein B-
100 are changed
prevents LDL
from effectively
binding to their
receptors on the
surface of cells
fewer LDLare
removed from the
blood
cholesterol
levels are much
higher than
normal
excess cholesterol
circulates through the
bloodstream, it is
deposited abnormally
in tissues and cause
HYPERCHOLESRTR
OLEMIA

PCSK9
• Several PCSK9 mutations can cause an
inherited form of hypercholesterolemia.
• These mutations change an amino acid in the
PCSK9 protein.
• The mutations are responsible for
hypercholesterolemia as "gain-of-function"
because they appear to enhance the activity of
the PCSK9 protein or give the protein a new,
atypical function.

LDLRAP1
More than 10 mutations in the LDLRAP1 gene have been
shown to cause a form of inherited high cholesterol called
autosomal recessive hypercholesterolemia.

LDLRAP1 gene
mutation
abnormally small,
non-functional of
LDLRAP1 protein or
prevent cells from
making any of this
protein
low-density
lipoprotein
receptors are
unable to LDL
from the
bloodstream
effectively
extra low-density
lipoproteins remain
in the blood
excess cholesterol
circulates through
the bloodstream, it
is deposited
abnormally in
tissues and may
cause
HYPERCHOLEST
ROLEMIA
extra LDL remain
in the blood.

DIAGNOSIS:
Clinical Diagnosis:
Blood tests are used to determine the cholesterol levels. The results of the
test will look like the following in FH patients:
Total cholesterol:
 in children, it will be more than 250 mg/dL
 in adults, it will be more than 300 mg/dL
LDL cholesterol:
 in children, it will be more than 170-200 mg/dL
 in adults, it will be more than 220 mg/dL
Also triglycerides must be tested, which are made up of fatty acids.
Triglyceride levels tend to be normal in patients with this genetic
condition. Normal results are below 150 mg/dL.
• Phenotypic and/or genetic tests that can
help find out if the patient has the
defective gene, or not.
• Testing the fibroblasts to see how
cholesterol is absorbed within the body

Cascade Testing
 Detailed family history ( At least 3 generations)
 DNA testing (For the patients with clinical diagnosis)
• If a mutation is identified genetic testing should be offered to all at risk – DO NOT
assess risk using LDL concentration.
• If found not to carry the gene then manage risk as in normal population
 If there is a clinical diagnosis but no mutation identified then use standardised LDL
concentrations to diagnose family members (Specialist)
 Consider screening all 1st and 2nd degree relatives and 3rd degree if possible.

Heterozygotes
• Dietary reduction of cholesterol has only
modest effects.
• The administration of bile-acid absorbing
resins, such as cholestyramine.
• This treatment is much more effective when
combined with one of the statin drugs (e.g.,
lovastatin, pravastatin), which reduce
cholesterol synthesis by inhibiting 3-hydroxy-
3-methylglutaryl coenzyme A (HMG-CoA)
reductase.
Homozygotes
• Liver transplants, which provide
hepatocytes that have normal LDL
receptors, have been successful in some
cases.
• Plasma exchange, carried out every 1 to 2
weeks, in combination with drug therapy,
can reduce cholesterol levels by about 50%.
However, this therapy is difficult to
continue for long periods.
• Somatic cell gene therapy, in which
hepatocytes carrying normal LDL receptor
genes are introduced into the portal
circulation, is now being tested.
TREATMENT

Medications for Hyperlipidemia
Drug Class Agents Effects (% change) Side Effects
HMG CoA reductase
inhibitors
Lovastatin
Pravastatin
LDL (18-55), HDL (5-15)
 Triglycerides (7-30)
Myopathy, increased liver
enzymes
Cholesterol absorption
inhibitor
Ezetimibe  LDL( 14-18),  HDL (1-3)
Triglyceride (2)
Headache, GI distress
Nicotinic Acid LDL (15-30),  HDL (15-35)
 Triglyceride (20-50)
Flushing, Hyperglycemia,
Hyperuricemia, GI distress,
hepatotoxicity
Fibric Acids Gemfibrozil
Fenofibrate
LDL (5-20), HDL (10-20)
Triglyceride (20-50)
Dyspepsia, gallstones,
myopathy
Bile Acid sequestrants Cholestyramine  LDL
 HDL
No change in triglycerides
GI distress, constipation,
decreased absorption of other
drugs

REFERENCES
 "Familial Hypercholesterolemia ." Familial Hypercholesterolemia. Web. 5 Dec. 2014.
<http://emedicine.medscape.com/article/121298-overview>.
 "Hypercholesterolemia." Genetics Home Reference. Web. 5 Dec. 2014.
<http://ghr.nlm.nih.gov/condition/hypercholesterolemia#genes>.
 "Chapter 3." Missense Mutation in the LDLR Gene: A Wide Spectrum in the Severity of
Familial Hypercholesterolemia. Web. 5 Dec. 2014.
<http://www.intechopen.com/books/mutations-in-human-genetic-disease/missense-mutation-
in-the-ldlr-gene-a-wide-spectrum-in-the-severity-of-familial-hypercholesterolemia>.
 Youngblom, Emily. Familial Hypercholesterolemia. U.S. National Library of Medicine, 1 Feb.
2014. Web. 5 Dec. 2014. <http://www.ncbi.nlm.nih.gov/books/NBK174884/>.
"Familial Hypercholesterolemia ." Familial Hypercholesterolemia. Web. 7 Dec. 2014. .

Familial hypercholesterolaemia

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