Homozygous Familial Hypercholesterolaemia: New Insights and Guidance for
Clinicians to improve Detection and Clinical Management
A Position Paper from the Consensus Panel on Familial Hypercholesterolaemia of the
European Atherosclerosis Society.
Marina Cuchel, Eric Bruckert, Henry N. Ginsberg, Frederick J. Raal, Raul D. Santos, Robert
A. Hegele, Jan Albert Kuivenhoven, Børge G. Nordestgaard, Olivier S. Descamps, Elisabeth
Steinhagen-Thiessen, Anne Tybjærg-Hansen, Gerald F. Watts, Maurizio Averna, Catherine
Boileau, Jan Borén, Alberico L. Catapano, Joep C. Defesche, G. Kees Hovingh, Steve E.
Humphries, Petri T. Kovanen, Luis Masana, Päivi Pajukanta, Klaus G. Parhofer, Kausik K.
Ray, Anton F. H. Stalenhoef, Erik Stroes, Marja-Riitta Taskinen, Albert Wiegman, Olov
Wiklund and M. John Chapman, for the European Atherosclerosis Society Consensus Panel
on Familial Hypercholesterolaemia.
Supplementary Information
Supplement to Figure 4
Phenotypic variability in HoFH. Genetic heterogeneity, in terms of mutation type, locus
heterogeneity, and co-inheritance of mutations across multiple genes, can translate to
phenotypic variability in HoFH.
Heterozygote mutations in APOB cause less severe autosomal dominant
hypercholesterolaemia than observed in HeFH due to LDLR mutations1,2, which translates to
a milder phenotype in homozygotes3,4. Mean LDL-C levels in homozygotes for PCSK9
gain-of-function mutations may be lower than those in homozygotes for LDLR mutations5.
Homozygotes for LDLRAP1 mutations have LDL-C levels similar to those in LDLRdefective HoFH patients, and atherosclerosis in these patients tends to be less severe6.
Double heterozygosity may also influence HoFH phenotype, e.g., double heterozygotes with
mutations in LDLR and APOB have higher LDL-C levels than patients with either mutation
alone, but lower levels than in patients with LDLR-defective HoFH7. Similarly, double
heterozygotes with mutations in LDLR and PCSK9 gain-of-function have LDL-C levels
roughly intermediate between those of HeFH and HoFH8,9. Finally, double heterozygotes
for LDLR and LDLRAP1 mutations seems to have LDL-C levels similar to those carrying
heterozygous LDLR mutations10; however, in a family in which disease-causing LDLR and
LDLRAP1 mutations segregated independently, members with a heterozygous LDLR
mutation combined with a homozygous LDLRAP1 mutation had more severe
hypercholesterolaemia than those with a homozygous LDLR mutation alone11.
References
1. Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R,
Averna M, Calandra S. Spectrum of mutations and phenotypic expression in patients with
autosomal dominant hypercholesterolemia identified in Italy. Atherosclerosis
2013;227:342-348.
2. Tybjaerg-Hansen A, Jensen HK, Benn M, Steffensen R, Jensen G, Nordestgaard BG.
Phenotype of heterozygotes for low-density lipoprotein receptor mutations identified in
different background populations. Arterioscler Thromb Vasc Biol 2005;25:211-215.
3. Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial
hypercholesterolemia. Nat Clin Pract Cardiovasc Med 2007;4:214-225.
4. Horinek A, Ceska R, Sobra J, Vrablik M. Familial defective apolipoprotein B-100
homozygote with premature coronary atherosclerosis. A case report. J Intern Med
1999;246:235-236.
5. Mabuchi H, Nohara A, Noguchi T, Kobayashi J, Kawashiri MA, Tada H, Nakanishi C,
Mori M, Yamagishi M, Inazu A, Koizumi J; Hokuriku FH Study Group. Molecular genetic
epidemiology of homozygous familial hypercholesterolemia in the Hokuriku district of
Japan. Atherosclerosis 2011;214:404-407.
6. Pisciotta L, Priore Oliva C, Pes GM, Di Scala L, Bellocchio A, Fresa R, Cantafora A, Arca
M, Calandra S, Bertolini S. Autosomal recessive hypercholesterolemia (ARH) and
homozygous familial hypercholesterolemia (FH): a phenotypic comparison. Atherosclerosis
2006;188:398-405.
7. Taylor A, Bayly G, Patel K, Yarram L, Williams M, Hamilton-Shield J, Humphries SE,
Norbury G. A double heterozygote for familial hypercholesterolaemia and familial defective
apolipoprotein B-100. Ann Clin Biochem 2010;47(Pt 5):487-490.
8. Pisciotta L, Priore Oliva C, Cefalù AB, Noto D, Bellocchio A, Fresa R, Cantafora A, Patel
D, Averna M, Tarugi P, Calandra S, Bertolini S. Additive effect of mutations in LDLR and
PCSK9 genes on the phenotype of familial hypercholesterolemia. Atherosclerosis
2006;186:433-440.
9. Noguchi T, Katsuda S, Kawashiri MA, Tada H, Nohara A, Inazu A, Yamagishi M,
Kobayashi J, Mabuchi H. The E32K variant of PCSK9 exacerbates the phenotype of familial
hypercholesterolaemia by increasing PCSK9 function and concentration in the circulation.
Atherosclerosis 2010;210:166-172.
10. Tada H, Kawashiri MA, Ohtani R, Noguchi T, Nakanishi C, Konno T, Hayashi K, Nohara
A, Inazu A, Kobayashi J, Mabuchi H, Yamagishi M. A novel type of familial
hypercholesterolemia: double heterozygous mutations in LDL receptor and LDL receptor
adaptor protein 1 gene. Atherosclerosis 2011;219:663-666.
11. Soufi M, Rust S, Walter M, Schaefer JR. A combined LDL receptor/LDL receptor
adaptor protein 1 mutation as the cause for severe familial hypercholesterolemia. Gene
2013;521:200-203.
Supplement to Lipoprotein apheresis
Accumulating data from apheresis registries and experience in large centres have confirmed
the clinical benefits of regular long-term lipoprotein apheresis in HoFH (see Supplemental
Table 1 and related references). Furthermore lipoprotein apheresis is cost-effective in HoFH,
more so in severe than in less severe phenotypes. In practice, the age of starting and the
frequency of treatment represent a compromise between practical feasibility, cost and the
clinical need to achieve LDL C target.
References
1. Watts GF, Gidding S, Wierzbicki AS, Toth PP, Alonso R, Brown WV, Bruckert E,
Defesche J, Lin KK, Livingston M, Mata P, Parhofer KG, Raal FJ, Santos RD, Sijbrands EJ,
Simpson WG, Sullivan DR, Susekov AV, Tomlinson B, Wiegman A, Yamashita S, Kastelein
JJ. Integrated guidance on the care of familial hypercholesterolaemia from the International
FH Foundation. Int J Cardiol 2014;171:309-325.
2. Health Quality Ontario. Low-density lipoprotein apheresis: an evidence-based analysis.
Ont Health Technol Assess Ser 2007;7:1-101.
Supplementary Table 1.
Impact of low-density lipoprotein apheresis on atherosclerotic cardiovascular disease in
children and young adults with homozygous familial hypercholesterolaemia: evidence
from case reports, studies and registries
Country
Canada
France
Germany
Reference
Al-Shaikh
(2002)1
Palcoux
2
[2008]
Keller
(2009)
3
Borberg
4
(2013)
Israel
Beigel
(2009)5
Dann
(2012)
6
No. of
patients
Apheresis
Interval
(weeks)
CVD on
treatment
First seen
0.3-12
years
2 (n=8)
1 (n=1)
3 patients
required
coronary
interventio
n; 2 died
from
coronary
artery
disease
Statin +
ezetimibe
8.5 ± 32
2 (n=24)
1 (n=2)
3 (n=1)
2 patients
suffered
angina
Statin
(n=9) +
ezetimibe
(n=6)
First seen
at 2
months to
28 years
1
8 patients
died due to
CVD
NA
After 32
years;
median
survival
45.6 years
LDL-C
(mmol/L)
Treatment
10 (9 with
apheresis)
At
diagnosis
12.2 -24
Statin +
cholestyra
mine,
colestipol
or niacin,
(5), or
probucol
(1)
27
Mean SD
at
diagnosis
22.9 ±
48.2
23
(16 with
apheresis)
At
diagnosis
15.2-27.4
7
NA
NA
Age at
beginning
(years)
NA
2
At
diagnosis
20.7-25.9
Statin
12-22
1-3
5
Before
apheresis
14.0-23.2
Statin
(n=3)
Statin +
ezetimibe
(n=2)
2.3-9 y
1 (n=3)
2 (n=2)
Mean SD
Statin +
Both
patients
died due to
CVD
(aged 35
and 42
years)
CIMT
studies
showed
full or
partial
resolution
of carotid
plaque in
4/5
patients at
6 years
Regression
in 4 and
stabilisatio
n in 7
Israel
Beigel
(2009)5
Dann
(2012)
Italy
Japan
6
Stefanutti
7
(2009)
Makino
8
(2003)
2
At
diagnosis
20.7-25.9
Statin
12-22
1-3
5
Before
apheresis
14.0-23.2
Statin
(n=3)
Statin +
ezetimibe
(n=2)
2.3-9 y
1 (n=3)
2 (n=2)
11
8
Mean SD
at
diagnosis
19.9±4.7
NA
Statin +
ezetimibe,
fibrate and
resins
NA
8.3
(3.5-15)
4-25
Both
patients
died due to
CVD
(aged 35
and 42
years)
CIMT
studies
showed
full or
partial
resolution
of carotid
plaque in
4/5
patients at
6 years
1-2
Regression
in 4 and
stabilisatio
n in 7
patients.
No clinical
events
during
treatment
(2-17
years)
1-2
One
patient
remained
free of
CVD
CIMT carotid intima-media thickness; CVD cardiovascular disease; LDL-C low-density
lipoprotein cholesterol; NA not available
Supplementary Table 1. Impact of low-density lipoprotein apheresis on atherosclerotic
cardiovascular disease in children and young adults with homozygous familial
hypercholesterolaemia: evidence from case reports, studies and registries, CONTD.
Country
Reference
Norway
Græsdal
(2012)9
Spain
FernándezFuertes
10
(2010)
Turkey
USA
Kardas
11
(2012)
Hudgins
12
(2008)
No. of
patients
LDL-C
(mmol/L)
Treatment
7
Median
(range) at
diagnosis
18.2
(15.3-32.8)
Statin +
ezetimibe
1
At
diagnosis
15.1
3
29
Before
apheresis
9.1-12.4
Mean SD
before
apheresis
13.5 ± 3.3
Statin
Statin
Statin +
ezetimibe;
5 with
porto caval
shunt
Age at
beginning
(years)
10 (6-44)
5.9
13-18
9 (3-15)
Apheresis
Interval
(weeks)
CVD on
treatment
1
CVD
progressed
in 6
patients
1
Decrease
in CIMT
over 2.3
years
2
Decrease
or
resolution
of
xanthomas
; no CVD
events
during 2
years
treatment
2-3
7 patients
discontinu
ed; 2 had
complicati
ons after
aortic
valve
replaceme
nt
Turkey
USA
Kardas
11
(2012)
Hudgins
12
(2008)
3
29
apheresis
9.1-12.4
Mean SD
before
apheresis
13.5 ± 3.3
Statin
Statin +
ezetimibe;
5 with
porto caval
shunt
13-18
9 (3-15)
2
2-3
xanthomas
; no CVD
events
during 2
years
treatment
7 patients
discontinu
ed; 2 had
complicati
ons after
aortic
valve
replaceme
nt
CIMT carotid intima-media thickness; CVD cardiovascular disease; LDL-C low-density
lipoprotein cholesterol; NA not available
References
1. Al-Shaikh AM, Abdullah MH, Barclay A, Cullen-Dean G, McCrindle BW. Impact of the
characteristics of patients and their clinical management on outcomes in children with
homozygous familial hypercholesterolemia. Cardiol Young 2002;12:105-112.
2. Palcoux JB, Atassi-Dumont M, Lefevre P, Hequet O, Schlienger JL, Brignon P, Roussel B.
Low-density lipoprotein apheresis in children with familial hypercholesterolemia: follow-up
to 21 years. Ther Apher Dial 2008;12:195-201.
3. Keller C. LDL-apheresis in homozygous LDL-receptor-defective familial
hypercholesterolemia: the Munich experience. Atheroscler Suppl 2009;10:21-26.
4. A. Borberg H. The lower the better: target values after LDL-Apheresis and semi-selective
LDL-elimination therapies. Transfus Apher Sci 2013;48:203-206.
5. Beigel R, Beigel Y. Homozygous familial hypercholesterolemia: long term clinical course
and plasma exchange therapy for two individual patients and review of the literature. J Clin
Apher 2009;24:219-224.
6. Dann EJ, Shamir R, Mashiach T, Shaoul R, Badian A, Stravets T, Kerzman Y, Finkelbaum
S, Gaitini D, Lorber A, Bonstein L. Early-onset plasmapheresis and LDL-apheresis provide
better disease control for pediatric homozygous familial hypercholesterolemia than HMGCoA reductase inhibitors and ameliorate atherosclerosis. Transfus Apher Sci
2013;49:268-277.
7. Stefanutti C, Vivenzio A, Di Giacomo S, Mazzarella B, Bosco G, Berni A. Aorta and
coronary angiographic follow-up of children with severe hypercholesterolemia treated with
low-density lipoprotein apheresis. Transfusion 2009;49:1461-1470.
8. Makino H, Harada-Shiba M. Long-term effect of low-density lipoprotein apheresis in
patients with homozygous familial hypercholesterolemia. Ther Apher Dial 2003;7:397-401.
9. Græsdal A, Bogsrud MP, Holven KB, Nenseter MS, Narverud I, Langslet G, Brekke M,
Retterstøl K, Arnesen KE, Ose L. Apheresis in homozygous familial hypercholesterolemia:
the results of a follow-up of all Norwegian patients with homozygous familial
hypercholesterolemia. J Clin Lipidol 2012;6:331-339.
10. Fernández-Fuertes LF, Martín MT, Plá IN, Novoa Mogollón FJ, Cremades JD. Lowdensity lipoprotein apheresis using double filtration plasmapheresis: 27-month use in a child
With homozygous familial hypercholesterolemia. Ther Apheresis Dialysis 2010;14:484–485.
[letter]
11. Kardaş F, Çetin A, Solmaz M, Büyükoğlan R, Kaynar L, Kendirci M, Eser B, Ünal A.
Successful treatment of homozygous familial hypercholesterolemia using cascade filtration
plasmapheresis. Turk J Haematol 2012;29:334–341.
12. Hudgins LC, Kleinman B, Scheuer A, White S, Gordon BR. Long-term safety and
efficacy of low-density lipoprotein apheresis in childhood for homozygous familial
hypercholesterolemia. Am J Cardiol 2008;102:1199-1204.