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Hanoi, 9 October 2016

Familial
Hypercholesterole
mia

Maurice Choo, MD, FACC


Prevalence of heterozygous FH
in Asia
❖

Estimated prevalence
based on frequency of
1:500 in population

❖

Assumes homogeneity
of gene frequency in
various populations

❖

Actual prevalence may
be as high in 1:80 in
some ethnic groups


Familial hypercholesterolemia

❖

High LDL cholesterol from early
childhood

❖

Cutaneous xanthomas and/or
arthritic symptoms by 3rd
decade of life

❖

Early onset and symptoms of
coronary heart disease

❖

Autosomal disorder affecting
1:300-500 (heterozygotes) and
1:1,000,000 (homozygotes)
persons in populations


Familial hypercholesterolemia Genotypes
❖

LDL receptor (LDLR)
genetic defects in most

❖

Familial defective
apolipoprotein B-100 in
5% of cases

❖

Mutations in the PCSK9
gene in 1% of cases


Diagnosis of heterozygous
FH
❖

Clinical diagnosis if LDL cholesterol >330 mg/dL

❖

Or tendon xanthomas and LDL >95th percentile

❖

Before adulthood, suspect if LDL >200 mg/dL

❖

TG levels usually normal or mildly elevated

❖

Likely homozygous FH if LDL >600 mg/dL

❖

Confirmation using LDL receptor analysis

❖

Prevalence of heterozygotes is about 1:300-500 persons

❖

Prevalence of homozygotes is about 1:1,000,000 persons


Main causes of secondary
hypercholesterolemia

❖

Diabetes mellitus

❖

Hypothyroidism

❖

Hepatic disease

❖

Renal disease


If identification of a cutaneous lesion is unclear, a biopsy can
be performed. Both xanthelasmas and the xanthomas of FH
contain accumulations of cholesterol. By contrast, eruptive
xanthomas in patients with severe hypertriglyceridemia
(levels >1000 mg/dL) contain triglycerides.

Xanthoma
and
xanthelasma


Differential diagnosis of familial
hypercholesterolemia

❖

Dysbetahyperlipoproteinemia (type III hyperlipidemia)

❖

Familial ligand defective apoB-100, familial defective apoB-100

❖

Homozygous autosomal recessive hypercholesterolemia

❖

Sitosterolemia (phytosterolemia)


Specialised tests for familial
hypercholesterolemia
❖

Lipoprotein electrophoresis is expensive and is unnecessary for the
diagnosis of FH. If fasting lipid analysis reveals elevated
triglyceride levels and the diagnosis of FH is in doubt, beta
quantification (ultracentrifugation and electrophoresis) may be
performed at a major lipid center.

❖

LDL receptor analysis can be used to identify the specific LDL
receptor defect. This can only be performed at certain research
laboratories and is expensive; and the results have no impact on
management. LDL receptor or apoB-100 studies can help
distinguish heterozygous FH from the similar syndrome of familial
defective apoB-100, but this finding would not alter treatment.


Imaging studies in familial
hypercholesterolemia

❖

Annual echocardiogram and carotid ultrasonography

❖

MSCT coronary angiography every 3-5 years

❖

Stress myocardial perfusion imaging if indicated

❖

Others - aorta and arterial imaging


Natural history of homozygous familial
hypercholesterolemia
❖

Female, born 13 October 1990, marked hypercholesterolemia

❖

Typical angina pectoris, at age 10, large multisite xanthomas

❖

CT coronary angiography, double vessel disease, at age 13

❖

Class 3-4 angina pectoris, severe diffuse triple vessel disease, at age 16

❖

Severe carotid disease (RICA 100%, LICA 90%, basilar 75-90% at age 17

❖

Successful LCCA-LICA stenting at age 17

❖

Plasmapheresis discussed but declined at age 18

❖

Non-Q anterior myocardial infarction at age 19

❖

Death two weeks before 20th birthday, following CABG

❖

Two siblings had earlier died from fatal MI before 18th birthday

Cholesterol mg/dL

LDL mg/dL

Homozygous familial hypercholesterolemia
800

600

400

200

0
2003

2004

Born Oct 1990

2005

2006

2007

2008

2009

2010
Died Sep
2010


Cholesterol

LDLc

TG

Heterozygous familial hypercholesterolemia
400
MSCT coronary
angiography normal
in June 2015

300
Atorvastatin &
Ezetimibe

200

100

0
2006
Born Feb 1996

2009

2013

2015


Cholesterol mg/dL

LDL mg/dL

TG mg/dL

HDL mg/dL

Heterozygous familial hypercholesterolemia
300
AMI and PCI, 1995
CABG, 2000
Recurrent ischemia, 2014

Diabetes mellitus, Type 2
Hypertension
Mild carotid artery disease

225

150

75

0
2007
Born Oct 1950

2009

2011

2013

2015


LDL targets in FH

❖

LDL <130 mg/dL for children

❖

LDL <100 mg/dL for adults

❖

LDL <70 mg/dL for adults with CAD and/or DM


Medications for homozygous

hypercholesterolemia
❖

Statins

❖

Bile acid sequestrants

❖

Ezetimibe

❖

Niacin

❖

Anti-PCSK9 monoclonal antibodies

❖

Mipomersen

❖

Lomitapide

❖

Estrogen replacement therapy

❖

Probucol


Alirocumab

The proprotein convertase subtilisin/kexin type 9 (PCSK9)
inhibitor, alirocumab is indicated as adjunct to diet and
maximally tolerated statin therapy for the treatment of adults
with heterozygous familial hypercholesterolemia or clinical
atherosclerotic cardiovascular disease, who require additional
lowering of LDLc. In one of several efficacy trials it reduces
LDLc by 58% compared with placebo by 24 weeks.


Evolocumab
Evolocumab is indicated as an adjunct to diet and other LDLlowering therapies (eg, statins, ezetimibe, LDL apheresis) for
the treatment of adolescent and adult patients with homozygous
familial hypercholesterolemia who require additional lowering of
LDLc. It is also indicated for heterozygous FH in adults.
Evolocumab plus standard therapy, as compared with standard
therapy alone, significantly reduced LDLc levels, and the rate of
cardiovascular events at 1 year was reduced from 2.18% in the
standard-therapy group to 0.95% in the evolocumab group
(hazard ratio 0.47; 95% confidence interval, 0.28 to 0.78;
P=0.003)

Mipomersen
Mipomersen is approved in the USA to treat homozygous
familial hypercholesterolemia. It reduces LDLc, non HDLc, and
apolipoprotein B. Mipomersen decreases hepatic and plasma
apoB as well as apoC-III. The compound is a secondgeneration antisense oligonucleotide, and can be administered
weekly. Mipomersen is not approved in Europe for the
treatment of homozygous and severe heterozygous FH
because of its risk profile, which includes cardiovascular risks,
malignancies, immune-mediated reactions, and hepatic
abnormalities.


Lomitapide

Lomitapide inhibits the microsomal triglyceride transfer
protein (MTP or MTTP) which is necessary for very lowdensity lipoprotein (VLDL) assembly and secretion in the
liver. It is approved as an adjunct to a low-fat diet and other
lipid-lowering treatments in patients with homozygous
familial hypercholesterolemia.


Bile acid sequestrants
❖

Anion-exchange compounds work by preventing reabsorption
of bile in the intestine, and modestly lower LDLc, and increase
HDLc and TG. Not absorbed systemically and, therefore, are
safer than most medications.

❖

Examples are cholestyramine, colestipol, and colesevelam.

❖

Useful in patients who cannot tolerate statins, who have
contraindications for statin therapy, or who request nonsystemic therapy


Procedures for homozygous
hypercholesterolemia

❖

LDL apheresis

❖

Portacaval anastomoses

❖

Liver transplantation

❖

Gene therapy

Liver transplantation

Liver transplantation is rarely performed because of the
considerable risks associated with the surgery itself and longterm immunosuppression. But a new liver provides functional
LDL receptors and causes dramatic decreases in LDLc levels.


Portacaval anastomosis

Portacaval anastomosis is less hazardous than liver
transplantation and requires no immunosuppression. Reduction of
LDLc by up to 50% can be achieved, often associated with
regression of coronary, aortic, vascular and cutaneous lesions.


LDL apheresis
LDL apheresis for homozygous FH involves selective removal of
lipoproteins that contain apo-B by heparin precipitation, dextran
sulfate cellulose columns, or immunoadsorption columns. All
methods reduce LDLc levels more than 50% and also lower
lipoprotein (a), VLDL, and triglyceride levels. HDL is spared. The
procedure takes 3 or more hours and is performed at 1- to 2week intervals. Few adverse events are experienced, most of
which are noncritical episodes of hypotension. LDL apheresis is
an extremely expensive procedure and is not readily available.