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Contents lists available at SciVerse ScienceDirect

Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis

Review

Homozygous familial hypercholesterolemia: Current perspectives

on diagnosis and treatment
Frederick J. Raal a, , Raul D. Santos b
a
b

Carbohydrate & Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
Lipid Clinic Heart Institute (InCor), University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil

a r t i c l e

i n f o

Article history:
Received 25 December 2011
Received in revised form 7 February 2012
Accepted 8 February 2012
Available online xxx
Keywords:
Familial hypercholesterolemia
Homozygous
Apolipoprotein B
LDL receptor

a b s t r a c t
Homozygous familial hypercholesterolemia (HoFH) is an autosomal co-dominant disease resulting from
mutations in both copies of the low-density lipoprotein receptor (LDLR) gene. Mutations in 3 other
associated genes, proprotein convertase subtilisin/kexin type 9, apolipoprotein B (APOB), and, more
rarely, the autosomal recessive hypercholesterolemia adaptor protein, may lead to a similar phenotype with varying severity. HoFH patients have aggressive cardiovascular disease that develops from
birth due to severe LDLR defects, resulting, in turn, in excess production of Apo B-containing atherogenic lipoproteins (low-density lipoprotein [LDL] and lipoprotein(a)). The condition is characterized by
exceptionally high LDL cholesterol levels, cutaneous and tendon xanthomas, and valvular and supravalvular stenosis, and accelerated atherosclerosis often manifests in the rst 2 decades of life. Treatment
typically involves lipid-modifying medical therapy as well as mechanical removal of plasma LDL by
means of apheresis. Although statins have afforded survival into the third and fourth decades of life,
further therapeutic advancements currently under investigation promise hope of further improvements
in survival and improved quality of life. The purpose of this review is to provide current perspectives
on diagnosis and therapy in an effort to encourage early recognition and treatment of this rare but
severe disease.
2012 Elsevier Ireland Ltd. All rights reserved.

Contents
1.
2.
3.
4.
5.
6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Denition and diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Natural history of HoFH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Current standard therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Future therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conict of interest and nancial disclosure statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction

Homozygous familial hypercholesterolemia (HoFH) is an inherited disorder caused primarily by homozygous mutations in the
low-density lipoprotein receptor (LDLR) gene. However, mutations
in 3 other genes regulating sterol and lipoprotein pathways may

Corresponding author at: Department of Medicine, Johannesburg Hospital, University of the Witwatersrand, 7 York Road, Parktown, 2193 Johannesburg, South
Africa. Tel.: +27 11 488 3538; fax: +27 11 643 2935.
E-mail address: frederick.raal@wits.ac.za (F.J. Raal).

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lead to similar phenotypes with varying severity: apolipoprotein B100 (Apo B-100), proprotein convertase subtilisin/kexin 9 (PCSK9),
and, more rarely, the autosomal recessive hypercholesterolemia
(ARH) adaptor protein [1]. Mutations in both LDLR alleles that result
in reduced uptake and clearance of low-density lipoprotein (LDL)cholesterol is the most common cause of HoFH. HoFH patients with
mutations in the LDLR gene may be true homozygotes (having the
same mutation in both LDLR alleles) or compound heterozygotes
(having different mutations on each LDLR allele). Patients with
HoFH present with severe hypercholesterolemia associated with
accumulation of LDL-cholesterol in plasma, tendons, and skin,
as well as present with accelerated atherosclerosis, particularly

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2
Table 1
Diagnostic criteria for HoFH from the literature.
Publication

Diagnostic criteria for HoFH

Seftel et al. [4]

Serum cholesterol concentration >14.3 mmol/L (550 mg/dL)

Appearance of xanthomas during rst decade of life
Hypercholesterolemia or clinical signs of hypercholesterolemia in both parents

Moorjani et al. [5]

Plasma cholesterol levels >550 mg/dL

Appearance of xanthomas at an early age
Detection of hypercholesterolemia in both parents

Haitas et al. [8]

Hypercholesterolemia in both parents (when available)

Total serum cholesterol >13 mmol/L (500 mg/dL) + presence of xanthomas in rst decade of life

Raal et al. [9,10]

Untreated serum LDL consistently >12 mmol/L

Appearance of xanthomas in rst decade of life
Hypercholesterolemia, or its clinical features, documented in both parents
Conrmation by DNA analysis for LDLR mutations

Goldstein [2]

Unique yellow-orange cutaneous xanthomas (frequently present at birth)

Tendon xanthomas, corneal arcus, generalized atherosclerosis during childhood
Plasma cholesterol >650 mg/dL in non-jaundiced child

Gagne et al. [11]

Two mutant alleles at LDLR conrmed by genetic testing or

LDL-C 220 mg/dL (5.69 mmol/L) while receiving lipid-lowering therapy at the highest tolerated dose (<15% response)
LDL-C >90th percentile in 2 rst-degree relatives
Presence of tendonous xanthomas and/or manifestations of premature coronary heart disease or corneal arcus

Marais et al. [12]

Childhood cutaneous or tendonous xanthomata

Total cholesterol >15 mmol/L (600 mg/dL)
Both parents should have severe hypercholesterolemia (>7.5 mmol/L or 300 mg/dL) or tendonous xanthomas
Family history of premature ischemic heart disease

Kolansky et al. [13]

Total cholesterol >500 mg/dL

Xanthomas at an early age
Presence of hypercholesterolemia in probands parents or other rst-degree relative

Marais et al. [14]

Clinical criteria:
Fasting LDL >500 mg/dL (12.9 mmol/L), triglycerides < 600 mg/dL (6.8 mmol/L)
Either xanthomata before age 10 years or FH in both parents
Genetic criteria: identication of 2 LDLR gene mutations
Functional criteria: <30% uptake compared to normal of LDL and up-regulated broblasts

Santos et al. [15]

Untreated LDL >500 mg/dL

Plus at least one:
Genetic testing conrmation of 2 mutated LDL-R alleles
Tendonous and/or tuberous xanthoma prior to age 10 years
Documented elevated LDL and both parents consistent with HeFH (LDL >200 mg/dL). If parent unavailable, history of CAD in
rst-degree relative (male <55 years or female <60 years of age)

Raal et al. [16]

Untreated LDL cholesterol >13 mmol/L

And either appearance of xanthomas before age 10 years or familial hypercholesterolemia in both parents

Mabuchi et al. [7]

Juvenile xanthomatosis with plasma cholesterol about 2 times that of parents or other family members with HeFH
Genetic diagnostic criteria: true homozygosity, compound heterozygosity, or double heterozygosity for FH genes

FH: familial hypercholesterolemia; HoFH: homozygous familial hypercholesterolemia; LDL-C: low density lipoprotein cholesterol; LDLR: low-density lipoprotein receptor.

coronary heart disease (CHD), often within the rst 2 decades of

life. In addition, HoFH patients frequently develop either valvular
or supravalvular aortic stenosis [2,3].
Globally, the prevalence of HoFH is estimated to be 1 case per 1
million persons, whereas the heterozygous form of familial hypercholesterolemia (HeFH) is estimated at 1 case per 500 persons [2].
The prevalence of HoFH is greater in specic regions throughout the
world, presumably due to founder effects and isolation of a population [1]. Among Afrikaners, the estimated prevalence of LDLR
mutations is 1 case per 100 persons for heterozygous patients and
1 case per 30,000 for homozygous patients [4]. Among French Canadians, the prevalence of HeFH is 1 in 270 and of HoFH is 1 in 275,000
[5]. The prevalence of HoFH is 1 in 100,000 among Lebanese persons [6]. The Hokuriku district of Japan has a prevalence 1 in 208
for HeFH and of 1 in 171,167 for HoFH [7].
Although in recent years there have been many publications
discussing FH, few have focused on HoFH and its unique clinical
prole. Here, we review the denition, diagnosis, natural history,
and recent and emerging therapies for HoFH.

2. Denition and diagnosis

Although the diagnostic criteria for HoFH are not uniform,
clinical diagnosis is typically based on the presence of xanthomas at an early age (<10 years), an untreated LDL-cholesterol
concentration >500 mg/dL (13 mmol/L) a treated LDL-cholesterol
concentration 300 mg/dL (7.76 mmol/L), or a non-high-density
lipoprotein (HDL)-cholesterol 330 mg/dL (8.5 mmol/L) (Table 1)
[2,4,5,716,18]. Interdigital xanthomas, particularly between the
thumb and index nger, are pathognomonic for HoFH (Fig. 1).
Except in the rare ARH, both parents will be obligate heterozygotes for familial hypercholesterolemia (FH) and will have elevated
LDL-cholesterol levels [16].
Genetic testing may be helpful for conrmation of HoFH, via
testing for more than 1600 unique allelic variants thus far described
in the LDLR gene [17]. However, genetic conrmation is not
usually required for accurate diagnosis and may remain elusive
in many patients, even after exhaustive searching for mutation
using current methods [6,18]. Many HoFH patients are actually

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Cumulative exposure (cholesterol yrs) by age:

FH vs. unaffected (healthy) individuals
HoFH

Unaffected
individuals

HeFH

Cholesterol year score, g/dL-years

10
Threshold
for CHD:
Reached by
age 20 in
for those
with HoFH;
>60 in
healthy
individuals

0
1
Fig. 1. Interdigital planar xanthomas in a young patient with homozygous familial
hypercholesterolemia.

compound heterozygotes, with 2 different mutant alleles at LDLR

[19]. Although less common, homozygous or heterozygous mutations in APOB, or rarely PCSK9 or ARH can lead to a similar
phenotype [18].
Cascade screening, through which relatives of a diagnosed
individual are screened for FH using a combination of serum cholesterol levels and mutation screening, is a means of obtaining early
diagnosis of FH in at-risk patients. This mechanism has been recommended by the National Institute for Health and Clinical Excellence
in the United Kingdom as a means of reducing morbidity and mortality due to heart disease through early diagnosis and effective
disease management [20].
3. Natural history of HoFH
In the typical individual with HoFH, high levels of plasma cholesterol are detectable at birth. It is believed that the high plasma
cholesterol levels represent both Apo B-containing lipoproteins,
LDL and lipoprotein(a) (Lp(a)). Lp(a) is composed of an LDL particle
with Apo(a) linked through Apo B and is a independent risk factor
for atherosclerosis in individuals with FH [21]. However, Lp(a) is
often resistant to statin therapy. Beginning at a very early age,
these high plasma levels lead to deposits of cholesterol in tendons,
cutaneous tissues, and cardiovascular tissues, including the aortic
root and valve [19]. In fact, a recent study showed fatty-streak
formation in fetal aortas and increased mortality associated with
maternal inheritance of FH caused by the V408M LDLR mutation,
suggesting that in utero exposure to hypercholesterolemia may
inuence disease progression and severity [22]. The extent of
these symptoms is typically age-dependent until the middle of the
second decade of life, at which point age becomes less relevant and
the prevalence of xanthomas and vascular disease is very high [8].
Severe and widespread atherosclerosis occurs in all major arterial
bedscarotid, coronary, femoral, and iliacand is often clinically
signicant at a young age [23]. The severity of atherosclerosis
tends to be proportional to the extent and duration of elevated
LDL-cholesterol levels, calculated as the cholesterol-year score
(Fig. 2) [24,25]. Children as young as 4 years old have suffered
sudden death due to acute myocardial infarction, with nearly
complete occlusion of the coronary artery [26]. Reports also exist
of patients as young as 10 years old who have required coronary
artery bypass surgery and have gone on to develop aortic stenosis
and carotid involvement [23,27].
Although severe coronary atherosclerosis is the major cause
of death, aortic stenosis has also been shown to be a key

20

40

60

80

Age (years)
Fig. 2. Cumulative low-density lipoprotein (LDL) exposure (expressed as grams
of cholesterol per year) over a lifetime in familial hypercholesterolemia patients
and normal individuals. Coronary heart disease occurs after a theoretical threshold of LDL exposure is exceeded (indicated by the horizontal solid black line).
This threshold is reached in early childhood in FH homozygotes and early middle
age in FH heterozygotes. CHD, coronary heart disease; FH, familial hypercholesterolemia; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous
hypercholesterolemia.
Adapted with permission from Horton et al. [25]. 2009 The American Society for
Biochemistry and Molecular Biology.

life-threatening complication in many individuals with HoFH

[28]. In these patients, thickening and discordance of the aortic
cusps typically evolves through lipid accumulation in combination
with inammatory cell inltration, much like histopathological
changes noted in non-FH populations with age-related calcic
aortic stenosis [26]. In young adults with HoFH, calcic aortic
stenosis often requires aortic valve replacement [8,28]. Despite
effective statin and LDL apheresis therapy to remove and/or lower
LDL, aortic calcication is almost universal [29]. The vascular
tissue near the aortic root is also affected [28]. Magnetic resonance
imaging (MRI) visualization (fat suppressed) of aortic root identied atherosclerotic plaque in 53% (9/17) of HoFH patients and
supravalvular aortic stenosis in 41% (7/17), with nearly all (6/7)
having evidence of plaques in the aortic root [30].
More recently, computed tomography coronary angiography
(CTCA) was shown to provide a non-invasive method for detecting early aortic and coronary atherosclerosis in HoFH patients
[15]. Calcied and mixed atherosclerotic plaques adjacent to
or compromising the coronary artery ostia were found in 5
of 5 asymptomatic HoFH subjects (3 females, 2 males; mean
age, 19.8 2.9 years; age range, 1523 years, with a mean LDLcholesterol of 618 211 mg/dL). All subjects had negative exercise
stress tests and myocardial scintigraphy examinations. Coronary
plaques causing signicant obstruction were found in 1 patient
(20%), who had previously undergone coronary artery bypass
surgery and aortic valve replacement at 15 years of age. Fig. 3 shows
the coronary ostial, as well as aortic plaque, distribution of 2 typical HoFH patients. In the absence of imaging, some clinical features
also correlate with the presence of atherosclerosis. Corneal arcus
has been associated with coronary disease severity [31]. Achilles
tendon width and age have been correlated with calcic atherosclerosis using a derivative of a quadratic equation [31]. However, to
avoid life-threatening valvular or supravalvular aortic stenosis, regular echocardiographic assessment of the aortic valve and root,
including measurement of the aortic gradient, must be performed.

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Fig. 3. Anterior (A and C) and posterior (B and D) views of 64-detector computed tomography angiography of 2 typical HoFH patients. Calcied plaques are seen in white,
whereas non-calcied plaques are depicted in yellow. Patient 1 (A and B) is a 21-year-old female who underwent coronary artery bypass graft and aortic valve replacement
at the age of 15 years and is homozygous for the low-density lipoprotein (LDLR) premature stop codon exon 8 mutation. Patient 2 is a 15-year-old asymptomatic male
homozygous for the LDLR ATC deletion isoleucine exon 3 mutation. The presence of calcied and mixed plaques in the aorta compromising both left and right coronary
ostiae can be seen in Patient 1 (A and B, arrow 1). The right coronary artery is totally occluded at its origin by mixed calcied and non-calcied plaques. In Patients 1 and 2,
calcied and mixed plaques are seen in ascending aorta and or in the aortic arch (A, B, and D, arrows 2 and 5). Plaques are seen adjacent to coronary origin in Patient 2 (C,
arrow 5) at the anterior view. In Patient 1, the left anterior descending artery and right coronary artery are lled by a patent saphenous bypass graft and the right internal
mammary artery, respectively (A and B, arrows 3 and 4). There are calcied non-occlusive plaques, respectively, in the right internal mammary artery and saphenous vein
graft of Patient 1 (A and B). (For interpretation of the references to color in this gure legend, the reader is referred to the web version of the article.)

Sufcient intervention to lower blood cholesterol levels in

HoFH patients is crucial for survival beyond young adulthood
[16,19]. However, because the risk for coronary atherosclerosis is
high and the disease progresses at a young age, it is imperative for
clinicians to assume that subclinical atherosclerosis is present and,
when possible, to use non-invasive imaging to monitor disease.
Recently, 2 prospective analyses evaluated CTCA imaging to detect
subclinical coronary atherosclerosis in patients with FH (not limited to HoFH) and found a high prevalence of subclinical disease.
In 102 HeFH subjects (mean age, 45 16 years; 64% females),
coronary plaques and luminal stenosis >50% were found in 48%
and 19% of studied patients, respectively [32]. Furthermore, in 140

FH subjects who had been treated with statins, 84% were found
to have detectable coronary plaques [33]. Nearly one-quarter
(33/140) were found to have obstructive coronary artery disease
(CAD) (>50% occlusion) [33].
Molecular variation has been shown to inuence the phenotype
in HoFH. FH is predominantly caused by mutations in the LDLR
gene. The severity of this autosomal dominant disease is not
only dose-dependent, related to the number of disrupted alleles
(heterozygosity vs. homozygosity), but is also dependent on the
function of the mutated receptor. A detailed review of many LDLR
mutations associated with HoFH showed a variety of mutations,
including: null mutations (no protein expression), ligand-binding

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site mutations, LDL-LDLR complex internalization mutations, and

mutations preventing LDLR recycling to the cell membrane [34].
Of the more than 1100 allelic LDLR variants identied so far,
severity of phenotypic expression is generally related to whether
the mutation wholly disrupts the receptor function or leads
to a reduction in functionwhether the phenotype is receptor
negative or receptor defective [35]. For instance, a severe HeFH
condition, inuenced by one or more mutations in one allele of
the LDLR or other FH-linked genes, has been shown to mimic
the HoFH phenotype [36]. HoFH patients who are LDLR negative
(<2% of LDL receptor function in cultured broblasts) tend to
have higher LDL-cholesterol levels and a worse prognosis than
those who are receptor defective (225% residual LDLR activity).
Untreated receptor-negative HoFH patients rarely survive beyond
the second decade of life. Those who are receptor defective have
a better prognosis but also often develop clinically signicant
atherosclerotic vascular disease by the age of 30 years. A low-fat
diet and optimizing other cardiovascular disease risk factors have
little impact on the course of the disease [3]. However, other
factors, environmental or genetic, may be involved in response to
lipid-modifying therapy, because identical molecular mutations
have been noted to result in varied response to treatment [9].
4. Current standard therapy
Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase
inhibitors or statins have greatly advanced treatment of FH,
including HoFH. Although patients with HoFH generally respond
to a lesser degree compared with HeFH individuals, response can
be seen, even in patients with receptor-negative genotype [9,10].
Due to the potential for intracellular cholesterol depletion and the
involvement of alternative pathways for LDL regulation in patients
with FH [37,38], statins may not be worthwhile in patients who
do not show a meaningful decrease in LDL levels. However, statin
therapy, even at a high dose, has been shown to be remarkably
safe in patients with HoFH [9,10,14]. Statins probably lower LDLcholesterol in HoFH by inhibiting hepatic cholesterol synthesis,
thereby limiting cholesterol available for the formation of Apo
B-containing lipoproteins in receptor-negative HoFH patients, and
by increasing residual LDLR activity in receptor-defective patients
[10]. However, as mentioned previously, statins do not effectively
decrease Lp(a) [39], thus early initiation of treatment, before
atherosclerosis becomes established, is key to current treatment
plans.
Statins may be started as early as in the rst year of life or at
initial diagnosis in patients with HoFH [19]. The goal of treatment
in pediatric FH patients is a 50% reduction in LDL levels that must be
met with a balance between increased statin dose, potential side
effects, and treatment goals. Ideally, all HoFH patients should be
referred to and managed by a lipid specialist, as most HoFH patients
will require LDL apheresis, if available, or should be considered
for liver transplantation [40]. In HoFH, statins, such as simvastatin, atorvastatin, and rosuvastatin, provide a range of decrease
in plasma LDL from 0% to 48%, with an average of about 15% for
receptor-negative individuals and about 26% for receptor-defective
individuals [12]. Actual improvement in values varies considerably
among individuals and depends on severity of initial LDL levels and
underlying genetic factors.
Simvastatin at various doses has been studied in 12 patients
with well-characterized HoFH. Patients were randomized to simvastatin 80 mg/day administered in 3 divided doses (n = 8; group
1) or 40 mg once daily (n = 4; group 2) [9]. After 9 weeks, group
1 had its total daily dose increased to 160 mg (divided doses),
and treatment continued for another 9 weeks. In patients receiving the 40 mg/day dosage, LDL-cholesterol concentrations fell by
14% (518449 mg/dL). Reductions at the higher doses were greater,

with a 25% (572422 mg/dL) mean reduction at the 80 mg/day

dosage and with a 31% (572391 mg/dL) mean reduction at the
160-mg/day dosage (P < 0.001) [9].
Atorvastatin (40 mg/day and 80 mg/day) was studied in 35 HoFH
patients. The 40 mg/day dosage reduced LDL-cholesterol levels by
17% (580480 mg/dL) compared with 28% (580422 mg/dL) with
the 80 mg/day dosage (P < 0.01) [10]. Reduction in LDL-cholesterol
in the 5 receptor-negative patients was similar to that achieved in
the 30 patients with residual LDLR activity [10]. In another study
comparing atorvastatin 80 mg/day and rosuvastatin 80 mg/day in
HoFH patients, those receiving atorvastatin who neither received
plasmapheresis nor had a portacaval shunt (n = 18) had a mean
(SE) percent reduction from baseline of 23 (2%) [14]. In similar
patients receiving rosuvastatin 80 mg/day (n = 28), LDL-cholesterol
was reduced by a mean of 26% from a baseline mean (SD) of
556.8 mg/dL (112.1 mmol/L) to 406 mg/dL (131.5 mmol/L) [14].
Other cholesterol-lowering medications in combination with
statins, such as ezetimibe, niacin, bile acid sequestrants, brates,
and omega-3 fatty acids, may have benets in addition to statin
therapy for the treatment of FH patients [41]. Because therapies
such as ezetimibe are not necessarily dependent on expression of
the LDLR, they may be particularly advantageous in patients with
HoFH [42].
A recent retrospective study reported the effect of lipidlowering therapy, mainly statin therapy, on time to rst major
cardiovascular event and on survival in a large cohort of HoFH
patients (n = 149). Despite achieving a mean reduction in LDLcholesterol of only 26%, lipid-lowering therapy was associated with
delayed cardiovascular events and prolonged survival [43].
In many countries, including the United States, Japan, and many
European countries, LDL apheresis is a treatment of choice for
patients with HoFH, particularly those refractory to statins [44,45].
LDL apheresis has been shown to have a benecial effect on aortic and coronary atherosclerosis [45]. It has also been shown to
reduce the risk of CAD in patients with HeFH. However, there
are no prospective, randomized studies reported that demonstrate
improved survival in HoFH. Moreover, cost, availability, length of
treatment session, and discomfort associated with apheresis limit
its use in all global settings, even for motivated HoFH patients.
Reductions in LDL and Lp(a) depend greatly on plasma volume
treated. Typical improvement in LDL-cholesterol is a reduction of
45%, with acute reductions ranging from 54% to 84% [19,46].
In patients with HoFH who are inadequately controlled on
statins alone, the current practice is to perform LDL apheresis at
weekly intervals to achieve the lowest possible LDL cholesterol levels [44,46,47]. Apheresis may be the best option for patients who
are resistant to or intolerant of statin therapy, and is generally recommended only in adults and children older than aged 7 years [47].
Apheresis reduction from baseline in LDL is 45%; adding statin therapy can sometimes reduce it a further 17% [11,46]. A key concern
with lipoprotein apheresis relates to optimizing the frequency of
apheresis given the noted rebound effect in serum cholesterol levels, in which levels rise rapidly in the days following treatment,
followed by slower rates of increase in the second week [45]. Given
that lipoprotein rates are not static with apheresis, recent focus
has been on how to apply LDL targets and correlating targets with
prevention of aortic and coronary atherosclerosis [45].
Advances in transplantation and related treatments, such as
immunosuppressant therapy, have improved survival rate for liver
transplantation in pediatric patients to approximately 90% at
5 years [48]. Liver transplantation is possibly curative for HoFH and
may be best performed as early as possible to limit vascular complications [48,49]. Given the reductions in risk and the potential
for cure for HoFH, several successful liver transplantations from
non-FH donors have been conducted in patients before appreciable vascular lesions appeared [48]. However, liver transplantation

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is limited by a lack of donor organs and the need for ongoing postoperative immunosuppression.
Other potential treatment options for HoFH, including portacaval shunting, partial ileal bypass surgery, and gene therapy, have
not been shown to be effective.
5. Future therapies
Several therapies under investigation may prove benecial for
treatment of HoFH. Mipomersen (ISIS 301012) is an antisense therapeutic that targets Apo B-100 mRNA [16,50]. In HoFH patients on
maximally tolerated pharmacological therapy (N = 51), the mean
percentage change in LDL-cholesterol was signicantly greater
with mipomersen (24.7%; 95% CI: 31.6 to 17.7) than with
placebo (3.3%; CI: 12.1 to 5.5; P < 0.001) [16]. However, the
response to mipomersen was highly variable, with some patients
achieving a reduction in LDL-cholesterol of 5080%, whereas others
failed to respond. The percent change from baseline in Lp(a) was
signicantly improved in the mipomersen-treated group (31.1%)
compared with placebo (7.9%; P = 0.001). The most common
adverse events were injection-site reactions, resulting in 2 patients
discontinuing therapy [16]. Twelve percent (4/34) of patients in the
mipomersen group, compared with none in the placebo group, had
an increase in the concentrations of alanine aminotransferase (3
times the upper limit of normal) [16]. The long-term safety and
effects of this medication are being evaluated not only in HoFH,
but also in subjects with severe HeFH and in subjects intolerant to
statin treatment.
Lomitapide (AEGR-733; BMS-201038), a microsomal triglyceride transfer protein (MTP or MTTP) inhibitor, interrupts
very-low-density lipoprotein assembly and secretion in the liver.
Lomitapide is currently completing a phase 3 trial in HoFH patients
maintained on a 10% low-fat diet (NCT00730236). Phase 2 results in
HoFH patients (N = 6) demonstrated that it reduced LDL-cholesterol
levels and Apo B levels by 50.9% and 55.6%, respectively, from baseline after 4 weeks of treatment (P < 0.001 for both comparisons)
[51]. However, no signicant changes were observed in Lp(a) levels.
Adverse events included elevation of liver aminotransferase levels
and gastrointestinal side effects, particularly increased stool frequency and marked accumulation of hepatic fat, which ranged from
less than 10% to more than 30% depending on the dose [51].
Other potential therapies include PCSK9 inhibitors, which target wild-type PCSK9 and may lead to increased expression of the
LDLR. Published results of PCSK9 inhibitors (antisense and monoclonal antibodies) in non-human primates demonstrate 5070%
reductions in circulating LDL that was transient with the antibody
inhibitor [52,53]. Preliminary results of an 8-week, phase 2 study in
humans suggest that a subcutaneously administered, fully human
antibody targeting PCSK9 (REGN727/SAR236553) in combination
with atorvastatin may achieve a 65% mean reduction in LDL compared with a 17% reduction with atorvastatin alone in patients with
primary hypercholesterolemia (no results reported in HoFH) [54].
6. Summary
HoFH is a rare disease, occurring in roughly 1:1,000,000 individuals, except in locations throughout the world that are at increased
risk due to a founder effect. HoFH, unlike other forms of hypercholesterolemia or HeFH, results in accelerated atherosclerosis at a
very young age, which leads to premature mortality. The primary
genetic basis for disease relates to mutations in both LDLR alleles. There is a great need for educational awareness around HoFH
and for early identication of potential sufferers. We propose a
consistent denition for diagnosis that is based on many similar
diagnostic criteria that have been described during the last 30 years

Fig. 4. Diagnostic denition of HoFH. APOB, apolipoprotein B; ARH, autosomal

recessive hypercholesterolemia; FH, familial hypercholesterolemia; LDL, lowdensity lipoprotein; non-HDL, non-high density lipoprotein.

(Fig. 4). Treatment has greatly beneted from newer-generation

statins, yet it remains limited in many patients who continue to
respond suboptimally, even at high doses of potent statins. There
remains a large, unmet need that will hopefully be improved with
upcoming medical modalities.
Conict of interest and nancial disclosure statement
Editorial and writing assistance in the development of this
manuscript was provided by Tracy Bunting-Early, PhD, of Publication CONNEXION (Newtown, PA). The manuscript was nancially
supported by Genzyme Corp. (Cambridge, MA). The authors meet
criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE), were fully responsible for
all content and editorial decisions, and were involved at all stages
of manuscript development.
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