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Consensus document on diagnosis and management of familial hypercholesterolemia from the Italian Society for the Study of

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Consensus

Consensus document on diagnosis and management of familial hypercholesterolemia from the Italian Society for the Study of

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Vicky Solari

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Nutrition, Metabolism & Cardiovascular Diseases (xxxx) xxx, xxx

Available online at [Link]

Nutrition, Metabolism & Cardiovascular Diseases

journal homepage: [Link]/locate/nmcd

POSITION STATEMENT

Consensus document on diagnosis and management of familial

hypercholesterolemia from the Italian Society for the Study of
Atherosclerosis (SISA)
Patrizia Tarugi a,*, Stefano Bertolini b,1, Sebastiano Calandra c, Marcello Arca d,
Francesco Angelico e, Manuela Casula f,g, Angelo B. Cefalù h, Laura D’Erasmo d,
Giuliana Fortunato i, Pasquale Perrone-Filardi j, Paolo Rubba k, Patrizia Suppressa l,
Maurizio Averna h,m, Alberico L. Catapano n,o
a
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
b
Department of Internal Medicine, University of Genoa, Genova, Italy
c
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
d
Department of Translational and Precision Medicine (DTPM), Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
e
Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
f
Department of Pharmacological and Biomolecular Sciences (DisFeB), Epidemiology and Preventive Pharmacology Service (SEFAP), University of Milan,
Milan, Italy
g
IRCCS Multimedica, Sesto San Giovanni (Milan), Italy
h
Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
i
Department of Medicina Molecolare e Biotecnologie Mediche, University of Naples Federico II and CEINGE Biotecnologie avanzate “Franco Salvatore”,
Naples, Italy
j
Department of Scienze Biomediche avanzate, Federico II University, Naples, Italy
k
Department of Internal Medicine and Surgery, Federico II University, Naples, Italy
l
Department of Internal Medicine and Rare Diseases Centre “C. Frugoni”, University of Bari A. Moro, Bari, Italy
m
Biophysical Institute CNR, Palermo, Italy
n
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milano, Italy
o
IRCCS Multimedica, Milano, Italy

Received 19 December 2023; received in revised form 4 April 2024; accepted 3 May 2024
Handling Editor: F. Galletti
Available online - - -

KEYWORDS Abstract Aims: Familial Hypercholesterolemia (FH) is a genetic disorder of lipoprotein meta-
Familial bolism that causes an increased risk of premature atherosclerotic cardiovascular disease
hypercho (ASCVD). Although early diagnosis and treatment of FH can signiﬁcantly improve the cardiovas-
lesterolemia; cular prognosis, this disorder is underdiagnosed and undertreated. For these reasons the Italian
Epidemiology; Society for the Study of Atherosclerosis (SISA) assembled a Consensus Panel with the task to pro-
Clinical and vide guidelines for FH diagnosis and treatment.
molecular features; Data synthesis: Our guidelines include: i) an overview of the genetic complexity of FH and the role
of candidate genes involved in LDL metabolism; ii) the prevalence of FH in the population; iii) the

Abbreviations: ADH, Autosomal Dominant Hypercholesterolemia; ApoB-100, Apolipoprotein B-100; APOE, Apolipoprotein E; ARH, Autosomal
Recessive Hypercholesterolemia; ASCVD, Atherosclerotic cardiovascular disease; CAC, Coronary artery calcium; CAD, Coronary artery disease;
CIMT, Intima-media thickening of common carotid arteries; CNV, Copy-number variants; CT, Computed tomography; CTCA, Computed to-
mography coronary angiography; DLCN, Dutch Lipid Clinic Network; FH, Familial Hypercholesterolemia; GOF, Gain of function; HDL-C, High
Density Lipoprotein cholesterol; HeFH, heterozygous FH; HoFH, Homozygous FH; LA, Lipoprotein apheresis; LDL-C, Low-density lipoprotein
cholesterol; LDLR, LDL receptor; LDLRAP1, LDL-Receptor Adaptor Protein 1; LOF, Loss of function; LIPA, Lysosomal Acid Lipase Deﬁciency;
NGS, Next-generation sequencing; PCSK9, Proprotein Convertase Subtilisin/Kexin Type 9; TG, Triglycerides.
* Corresponding author. Patrizia Tarugi, Department of Life Sciences, University of Modena and Reggio Emilia, via G. Campi 287, 41121 Modena,
Italy.
E-mail address: tarugi@[Link] (P. Tarugi).
1
Deceased during the preparation of the manuscript.

[Link]
0939-4753/ª 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical
Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

clinical criteria adopted for the diagnosis of FH; iv) the screening for ASCVD and the role of cardio-
Atherosclerotic
vascular imaging techniques; v) the role of molecular diagnosis in establishing the genetic bases of
cardiovascular
the disorder; vi) the current therapeutic options in both heterozygous and homozygous FH. Treat-
disease;
ment strategies and targets are currently based on low-density lipoprotein cholesterol (LDL-C)
Cholesterol-lowering levels, as the prognosis of FH largely depends on the magnitude of LDL-C reduction achieved by
therapies lipid-lowering therapies. Statins with or without ezetimibe are the mainstay of treatment. Addition
of novel medications like PCSK9 inhibitors, ANGPTL3 inhibitors or lomitapide in homozygous FH
results in a further reduction of LDL-C levels. LDL apheresis is indicated in FH patients with inad-
equate response to cholesterol-lowering therapies.
Conclusion: FH is a common, treatable genetic disorder and, although our understanding of this
disease has improved, many challenges still remain with regard to its identiﬁcation and
management.
ª 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian
Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II Uni-
versity. Published by Elsevier B.V. All rights are reserved, including those for text and data mining,
AI training, and similar technologies.

1. Introduction the recruitment of the LDLR in clatrin coated pits on the

cell membrane of hepatocytes and its cellular internali-
The definition of Familial Hypercholesterolemia (FH) in- zation (Table 1 and Fig. 1) [6].
cludes disorders with a semi-dominant or recessive pattern The molecular complexity of FH derives from the fact
of inheritance, which were formerly defined as Autosomal that the causative variants in candidate genes can be
Dominant Hypercholesterolemia (ADH) and Autosomal present in 1 allele (heterozygous genotype) or in 2 alleles
Recessive Hypercholesterolemia (ARH). Regardless of the (homozygous genotype). Furthermore, the homozygous
type of transmission, these disorders are characterized by genotype can involve only one candidate gene (mono-
elevated plasma levels of low-density lipoprotein choles- genic) or two different genes (digenic).
terol (LDL-C) from birth, resulting from defects in the The molecular characterization of a large number of ADH
mechanism responsible for the receptor-mediated hepatic patients has shown that >90% of them have a LOF variant of
removal of LDL particles from plasma [1e4]. LDLR gene. More than 2500 variants of this gene have been
The genes involved in ADH include: 1) LDLR encoding annotated in the available data-bases. LOF variants of APOB
the LDL receptor (LDLR) (ADH-1); 2) APOB, encoding the gene which block the binding of LDL to LDLR have been found
apolipoprotein B-100 (apoB-100), the major protein in 3e8% of FH patients. Fewer than 1% of patients have been
component of LDL, responsible for the binding of LDL found to carry a GOF variant of PCSK9 gene, resulting in an
particles to LDLR (ADH-2); and 3) PCSK9, encoding Pro- increased lysosomal degradation of LDLR and in defective
protein Convertase Subtilisin/Kexin Type 9 (PCSK9), a receptor-mediated hepatic uptake of plasma LDL [1,5].
protein that promotes the intracellular degradation of the Several pathogenic LOF variants of LDLRAP1 gene were re-
LDLR (ADH-3). ADH is caused by loss of function (LOF) ported in the rare patients with ARH [6,7].
variants of LDLR and APOB genes or gain of function (GOF) There are other genetic disorders of lipid metabolism
variants of PCSK9 gene (Table 1 and Fig. 1) [1,5]. mimicking the FH phenotype such as: Sitosterolemia
ARH is due to LOF variants of LDLRAP1 gene which (ABCG5 or ABCG8 gene variants) [8e10] and Lysosomal
encodes the LDL-Receptor Adaptor Protein 1, involved in Acid Lipase Deficiency (LIPA gene variants) that are due to

Table 1 Genes associated with primary monogenic cause of high plasma levels of LDL cholesterol.

Genes Chr. Pathogenic Variant type Inheritance Prevalence of gene

variants variants in FH patients
Classic FH LDLR 19p13.2 >2500 LOF AD (ADH-1) 92e94%
APOB 2p24.1 w16 LOF AD (ADH-2) <5%
PCSK9 1p32.3 w32 GOF AD (ADH-3) <0.5%
LDLRAP1 1p36.11 w25 LOF AR (ARH) <1%
FH phenocopies APOE 19q13.32 2 LOF AD <<<0.1%
ABCG5 2p21 w45 LOF AR (Sitosterolemia) <<<1%
ABCG8 2p21 w60 LOF AR (Sitosterolemia) <<1%
LIPA 10q23.31 w100 LOF AR (Lysosomal Acid <1%
Lipase Deﬁciency)
Chr: Chromosome, AD: Autosomal dominant, ADH: Autosomal dominant hypercholesterolemia, AR: Autosomal recessive; ARH: Autosomal
recessive hypercholesterolemia, LOF: loss of function, GOF: gain of function.

Figure 1 Effect of pathogenic variants of major candidate genes in Autosomal Dominant Hypercholesterolemia (ADH) and Autosomal
Recessive Hypercholesterolemia (ARH).
ADH-1 is due to loss of function variants in LDLR gene that disrupt the activity of the LDL receptor (LDLR). ADH-2 is due to loss of function variants in
the APOB gene that reduce the binding of LDL to the LDLR. ADH-3 is due to gain of function (GOF) variants in PCSK9 gene which increase the capacity
of PCSK9 to induce the lysosomal degradation of the internalized LDLR. ARH is due to loss of function variants in LDLRAP1 gene that disrupt the
activity of an adaptor protein involved in the positioning of the LDLR on the coated pits of the plasma membrane.

defects of cholesterol metabolism not primarily related to from 1.46% to 0.18% in the general population [26e28]
the LDLR pathway [11]. Only few patients are affected by and from 2.3% to 3.5% among statin-treated patients
these conditions as the lipid phenotype is present only in [26,29].
homozygotes. Recently, patients with FH-like phenotype Meta-analyses clearly show how this prevalence is
with dominant transmission have been found to carry two higher in subgroups of subjects with premature ASCVD.
extremely rare LOF variants of APOE gene [12,13]. Indeed, a recent study showed that HeFH prevalence is 20-
Finally, it should be emphasized that a large percentage fold higher among those with premature ASCVD, and 23-
of adult subjects with primary hypercholesterolemia do fold higher among those with severe hypercholesterolemia
not have a readily identifiable defect in the known [25]. Accordingly, data from the POSTER study on patients
candidate genes (they are designated phenotype positive/ with a recent ASCVD or a planned revascularization pro-
genotype negative subjects) [1,5]. It has been reported that cedure [30], and from the START Registry on patients with
a variable proportion of these subjects has inherited a stable coronary artery disease (CAD) reported a prevalence
combination of common genetic variants raising LDL-C of 1 in 20e40 [31].
(polygenic inheritance) whose additive effect would The prevalence in the paediatric population is also
result in a “phenocopy” of FH [14e16]. poorly documented. Estimates from meta-analyses are
Another genetic condition of hypercholesterolemia may comparable to those in adults (0.28%e0.36%) [23]. Expe-
be related to the elevation of lipoprotein (a) [Lp(a)], an LDL riences from some systematic screening programs report a
sized particle covalently linked to the unique glycoprotein prevalence of 0.1e0.3% [32,33]. An Italian experience of a
apo(a) [17e19]. screening program suggested that 17.2% of a cohort of
unrelated hypercholesterolemic children (TC > 90
2. Epidemiology of familial hypercholesterolemia percentile), on the basis of familial phenotype, could have
been classified as probable HeFH, with genetic confirma-
Historically, the prevalence of heterozygous FH (HeFH) was tion obtained in about half of these children [34].
considered to be 1 in 500 persons, as mathematically The homozygous form of FH (HoFH), on the other hand,
derived by the prevalence of the rarer homozygous form of is much rarer. Estimates on the Italian population sug-
FH detected in the London population [20]. In the past gested a prevalence between 1:350,000 and 1:450,000
decade, this estimate has been refined mainly by the evi- [8,35]. In Italy, we found a high prevalence, about
dence from Danish population studies becoming higher 1:40,000, of the ARH in the island of Sardinia [36], likely
than previously thought [21,22]. Later on, these findings caused by a combination of genetic drift, consanguinity,
were confirmed in other populations and large meta- and geographic isolation [37].
analyses have determined that the global prevalence of Meta-analyses also show a high variability of preva-
HeFH is 1 in w250e300 in most populations [23e25]. lence estimates, partly due to the different geographical
Prevalence data in Italy are scarce, mainly due to the and ethnic origin of the populations included, but mostly
lack of systematic screening programmes in the general related to the criterion for defining the disease, which can
population. Some local experiences, respectively using a be diagnosed either on a clinical or genetic basis. Since the
cut-off of LDL-C 190 mg/dL or the Dutch Lipid Clinic presence of a pathogenic variant has been described in
Network (DLCN) criteria, reported estimates that range 30e80% of clinically diagnosed individuals [38] and since

knowledge of the genetic basis of the disease is still simplest, and least expensive [47], is the cascade
evolving [39], it is not surprising that estimates of HeFH in screening, i.e. the investigation of first-degree relatives of a
the general population vary from 0.12% to 1.2% (overall person diagnosed with FH, especially when the diagnosis
pooled prevalence 0.40%) (BOX 1) [24]. is confirmed by genetic testing. This approach plays a key
In Italy, FH shows a highly heterogeneous genetic role especially in pediatric age, as in this age group the
background. However, several pathogenic variants were clinical features of the disease are often still poorly man-
recurrent in unrelated patients, leading to the identifica- ifested [48]. In most cases, FH subjects are identified
tion of more than ten LDLR clusters, as for example that through opportunistic screening, often starting with the
represented by carriers of the c.1646G > A, p. (G549D) (FH finding of elevated cholesterol levels or following the
Palermo-1) mutation, including 78 families mainly development of a cardiovascular event at an early age,
distributed in the southern regions of mainland Italy and especially if accompanied by a family history of hyper-
in Sicily, c.662 A > G, p. (D221G) (FH Padua-1) mutation, cholesterolemia or cardiovascular events. The main limi-
including 97 apparently unrelated families mostly tation for this approach is the strict dependence on the
distributed in the north-east areas of Italy, the sensitivity and awareness of the clinician, whether general
c.1415_1418dupACAT, p. (Q474Hfs*63) (FH Savona-1) mu- practitioner, pediatrician, endocrinologist, cardiologist or
tation, including 52 families in the Liguria region [40], the others [49,50]. Electronic extraction tools and clinical alert
c.1775G > A, p. (G592E) (FH Foggia-1) mutation, described systems, integrated into digital health information sys-
in 40 families in Southern Italy [41], and the c.2312-3C > A, tems, could be useful in the identification of index cases
p. (A771_I796del) (FH Naples-8) mutation, described in 39 [26]. Finally, one possible approach is systematic screening
families of the Campania region [42]. at pre-school or school age. It is certainly more demanding
in terms of resources, but has been proven to be cost-
3. Screening approaches effective [51], as demonstrated by the example of
Slovenia in Europe [52]. Results from the implementation
In HeFH and HoFH the exposure to high and very high LDL- of different strategies in different countries suggest that a
C levels respectively starts at birth and clinicians can combination of different approaches is probably the most
calculate for each FH patient the LDL-C burden (years of effective way to enhance FH diagnosis. However, screening
exposure multiplied by average LDL-C) [43]. The clinical modalities need to be tailored to fit different economic,
consequences of a such high LDL-C burden are: i) the ac- social and health system contexts.
celeration of atherogenesis and the anticipation of the
clinical cardiovascular events in comparison with the non- 4. Molecular diagnosis of FH patients
FH subjects; ii) the need to identify the FH patients,
especially the FH children, in order to start, as early as 4.1. Molecular analysis
possible, the therapeutical interventions [44].
The effectiveness of cardiovascular prevention in in- Despite clinical diagnosis may identify FH patients allow-
dividuals with FH is strictly dependent on the timing of ing for an immediate treatment, molecular diagnosis is
diagnosis: the earlier the patient is diagnosed the earlier mandatory to: 1) confirm the diagnosis; 2) define the ge-
treatment can be started and a better the clinical prognosis netic status; 3) start the cascade screening.
is expected. For this reason, various screening approaches Next-generation sequencing (NGS) improved the ge-
have been proposed and implemented [45,46]. The netic analysis of FH patients allowing to analyze several
genes at the same time. Two NGS approaches are possible:
one based on a FH-specific gene panel and another one
based on exome sequencing enabling the sequence of
coding regions of all genes while focusing the variant
BOX 1 analysis on causative genes [53]. NGS should be set-up
Epidemiology of FH with a high coverage allowing the detection of copy-
number variants (CNV) at least in the LDLR gene,
FH is not a rare disease. It is important for although in very rare cases CNVs in the other causative
doctors, paediatricians and specialists to be genes can be the FH pathogenic cause, such as in the case
aware that HeFH can affect: of the whole PCSK9 gene duplication [54]. The genetic
analysis of FH and methodological limitations are reported
1 in w250e300 of adult patients in Fig. 2.
1 in 20e40 of adult patients with hyper- Due to the partial phenotypic overlap between HeFH
cholesterolaemia (LDL-C >5.0 mmol/L, >190 and HoFH, the genetic status of patients should be accu-
mg/dL) or with coronary artery disease rately defined by the status of variants as follows: 1) in
1 in 6 of pediatric patients with hyper- case of presence of 2 different variants in the same gene,
cholesterolaemia (total cholesterol >90 the analysis of variant segregation should be performed to
percentile, 4.9 mmol/L, 190 mg/dL) determine if the 2 variants are present on the same allele
(heterozygous variant) or on different alleles (bi-allelic
also known as “compound heterozygous variants”); 2) in

Figure 2 Genes and analytical approach for the genetic screening of FH.
Next-generation sequencing (NGS) should be set-up to detect small variants in the coding region and exon-intron boundaries (at least 10 intronic
bases) of indicated genes and the copy number variants (CNVs) at least in the LDLR gene. CNV of LDLR gene could be eventually evaluated by
Multiplex Ligation-dependent Probe Ampliﬁcation (MLPA) (ADH, Autosomal Dominant Hypercholesterolemia; ARH, Autosomal Recessive
Hypercholesterolemia.

case of detection of 2 copies of the identical variant (“true” 4.3. Genetic report
or “simple” HoFH), the homozygous status cannot be
directly established; in fact, it should be verified the Genetic reports should clearly indicate the methodology
absence of CNVs including the region of the variant to used, the results obtained as well as specific comments on
exclude a possible hemizygous/compound heterozygous each single case. Table 2 lists the main aspects to be taken
status. If this is not possible by the methods employed, a into account when drawing up the genetic report of a
segregation study should be performed to verify that the patient with FH.
variant is present in both patient’s parents.
The polygenic score for high LDL-C should be calculated 4.4. Genotype-phenotype correlations
in patients without rare variants in causative genes
because it could represent a genetic basis of the hyper- The identification of a pathogenic variant helps to estimate
cholesterolemia in a large number of patients [55]. the cardiovascular risk assessment because among patients
with the same LDL-C level, cardiovascular risk was found to
4.2. Pathogenicity evaluation be higher in carriers of a pathogenic variant than in non-
carriers [58]. The identification of the variant type and the
An accurate pathogenicity evaluation is mandatory to correct definition of the genetic status (HeFH or HoFH) can
correctly define the patient’s genotype, in order to claim also improve risk stratification [59]. The different aspects of
the variant pathogenicity only in case of scientific evi- FH genetics and of their correlation with phenotype are
dences. Variants should be evaluated according to the reported in Table 3 [40,41,58,60e66,70].
American College of Medical Genetics (ACMG) guidelines
considering the FH-specific suggestions by Chora et al. 5. Clinical diagnosis of familial hypercholesterolemia
[56]. The ClinGen consortium also improved the patho-
genicity evaluation of LDLR variants [57]. As example, Several clinical diagnostic criteria exist to define the
assigning the pathogenicity criterion related to the variant probability that a given subject is affected by FH. In
presence in databases it is not only based on the absence particular, the age of first detection of high LDL-C levels
of the variant, but also on its presence with a low fre- (>5.0 mmol/L in adults and >3.5 mmol/L in children;
quency, because of the high frequency of FH. >190 mg/dL and >135 mg/dL, respectively), the presence
Databases containing pathogenic variants (HGMD pro- of tendon xanthoma and premature ASCVD manifesta-
fessional, ClinVar and LOVD) with related scientific evi- tions, and positive family history have to be considered
dence (specific functional studies, co-segregation of variant key to the diagnosis [1]. All the information of clinical
with phenotype, etc.) should be consulted in order to history is useful to build up a score (e.g. DLCN score),
correctly evaluate. Recently, a database of LDLR variants which gives an overview of the cardiovascular risk condi-
with a pathogenicity classification approved by the ClinGen tion of the patient. Other diagnostic indexes may be used
FH Variant Curation Expert Panel was created; all included for the clinical diagnosis of FH beside the DLCN criteria,
variants were revised by the experts and have been Simon Broome system [67], and World Health Organiza-
marked as FDA-approved ([Link] tion (WHO) [68]. According to 2019 ESC/EAS Guidelines for
affiliation/50004/#heading_documents). the management of dyslipidaemias [63], the use of DLCN

Table 2 Aspects relevant to patient diagnosis to be highlighted in the genetic report.

Section Notes Potential implications for physicians/

laboratory
Methods Used methodology should be described in order to It allows to establish if the genetic
infer the procedure limits i.e. not analyzed genes, screening should be extended.
low coverage preventing CNV detection, etc.
Method limits should also be specified in the
genetic report.
Results Variants should be reported according to the It allows to correctly identify the variant
current official nomenclature of the Human for cascade screening and for variant
Genome Variation Society (HGVS -[Link] analysis in databases.
[Link]/).
Pathogenicity assessment should be reported in It allows to correctly define the genetic
order to understand the variant role in the disease status of the patient.
development.
Variant of uncertain significance (VUS) should be Patients with VUS could be easily
reported because several variants are classified as reclassified as patients with pathogenic
VUS due to lack of evidences and future studies variants.
could reveal their pathogenicity.
In case of detection of two different variants, if no It allows to correctly define the patient’s
segregation study was performed, a precautionary genotype as HeFH or HoFH.
sentence should report that the identified variants
could be present both on the same allele or on the
two different alleles, preventing the correct
definition of the HeFH or HoFH status.
In case of detection of a variant at homozygous The identification of an allele with a
status, if the method not allowed to verify the deletion is important for performing
absence of CNV or if no segregation study was cascade screening.
performed, a precautionary sentence should report
that the patient could be both a homozygote or a
compound heterozygote due to an eventual CNV
including the region of the variant.
Conclusions/additional In case of detection of a pathogenic variant, the The genetic report may induce the
comments screening of patient’s relatives should be patient or the patient’s doctor to perform
recommended. In case of biallelic variants the molecular analysis of relatives, thus
(homozygous or compound heterozygous status), it identifying additional FH patients.
should be clearly indicated that all patient’s
children will be obligate HeFH.
In case of patients without pathogenic variants, the It allows to establish if the genetic
report should clearly indicate that additional screening should be extended.
causative variants could be present in relation to
the method limits.

score for the clinical diagnosis of FH is recommended. 6. Recommendations for diagnosis and clinical
Patients with definite clinical diagnosis of FH early deserve evaluation of heterozygous familial
intensive lipid lowering therapy because high LDL-C levels hypercholesterolemia
are the driver of an increased cardiovascular risk despite a
genetic diagnosis. 6.1. Clinical evaluation
It has been reported that 60e80% of patients with
clinically-defined “definite” FH, are found to be positive at There are several clinical data that can be useful to raise
the molecular diagnosis, whereas in patients with “prob- suspicion of FH. They are listed in BOX 2 and must be al-
able” FH only 21e44% are found to be positive. Addition- ways part of the clinical screening in a patient with sus-
ally, the LDL-C level is “crucial”, as the probability of pected FH. Nevertheless, the presence of other major
finding a causative variant in FH-candidate genes is higher cardiovascular risk factors (diabetes mellitus, smoking
in the presence of extremely elevated plasma LDL-C levels habits, arterial hypertension) as well as the exclusion of
[1]. It should be emphasized that an FH phenotype as secondary hyperlipidemias should be performed. Routine
defined by the currently used clinical diagnostic criteria biochemistry results would be useful in this context.
(e.g. DLCN, Simon Broome) can have different genetic Plasma triglycerides (TG), high density lipoprotein
causes (monogenic/digenic, polygenic or multifactorial). To cholesterol (HDL-C), apoB and Lp(a) concentration mea-
take into account this heterogeneity the term “FH syn- surements should be included in the baseline lipid panel of
drome” has been proposed [69]. a FH patient.

Table 3 Features of FH genetics which impact on the diagnosis and management of the FH patients.

Genotype-phenotype correlations Clinical consequences

Presence of a pathogenic variant: 1) confers increased Patients with a FH-causative variant should be considered at
cardiovascular risk [58,70]; 2) is associated with higher LDL- high cardiovascular risk according to the EAS guidelines [63].
C levels in adults and children [60e62].
Patients with 2 pathogenic variants (HoFH) show a worse Based only on the LDL-C levels an accurate differentiation
phenotype than HeFH [60]. However, an overlap of LDL-C between HeFH and HoFH cannot be made. Molecular analysis
levels can be observed among patients with 2 variants and enables to determine the genetic status, allowing to identify
patients with one variant. HoFH needing stronger therapies.
Among different variant types, patients with null variants The identification of the causative variant and of the
show a worse phenotype than patients with defective associated degree of protein impairment allows for a
alleles. In some cases, HeFH patients with a null allele show prognostic evaluation of patient cardiovascular risk.
a phenotype similar to HoFH patients [58].
Patients with pathogenic variants in the LDLR gene show a
worse phenotype than patients with pathogenic variants in
other genes [62].
Patients with FH-causative variants (monogenic FH) and The search for variants in FH-phenocopies can help to identify
heterozygote for variants in FH-phenocopy genes (oligogenic patients predisposed to develop more severe
FH) show a worse phenotype than monogenic FH [64]. hypercholesterolemia than monogenic FH patients.
A large variability of phenotypes was observed among The presence of a variant could lead to different LDL-C levels
patients sharing the same variant/variant type [41,60]. among patients sharing the same variant in a family
Incomplete penetrance was observed among HeFH carrying Within a family, not all members with the pathogenic variant
APOB variants functionally proved to cause decreased LDL in the APOB gene will develop hypercholesterolemia
binding to LDLR [65].
Presence of a founder effect in specific geographic areas lead There is a high probability of genetically determined FH in
to a high prevalence of specific genetic variants, also regions with a founder effect of FH-causative variants,
explaining a high frequency of FH [40,66]. implying the need of a wider approach of molecular screening.

BOX 2
To better define the exposure of the patient to high LDL- Clinical work-up in FH patients
C concentrations, it is useful to collect information on the
degree of control of hypercholesterolemia in the past years Clinical History
in relation to drug interventions and lifestyle changes.
Further investigation should involve patient’s relatives to LDL-C levels (patients and relatives, first de-
establish: i) LDL-C levels; ii) presence of xanthoma and gree) e Age of detection of high LDL-C and
ASCVD events. The age of occurrence of first clinical mani- time of exposure (patients)
festations of cardiovascular disease should also be recorded History of high LDL-C (patients) - History of
(BOX 2). drug management
The presence of xanthoma should be systematically Cigarette smoking, Blood Pressure, Diabetes
searched in patients with suspected FH. Also the type mellitus
(tendons, cutaneous planar or tuberous) and sites (Achilles Exclusion of secondary hypercholesterolemia e
tendons, hand extensors tendons, interdigital, knees, el- Routine biochemistry e TG, HDL-C, ApoB, Lp(a)
bows, other sites) of xanthoma need to be described. The Xanthoma (type, sites, age of detection) and
thickness of Achilles tendons should be evaluated by Corneal arcus (patients and relatives)
palpation, with the awareness of the availability of echo- Clinical Cardiovascular disease (MI, Stroke,
graphic methods that are very sensitive for detection and PVD, Aortic aneurism) e Age of first event
useful for the follow up of local cholesterol accumulation. Use of DLCN criteria
Corneal arcus is of diagnostic interest in younger patients,
while in older ages (>70 years) it represents a nonspecific Clinical examination
clinical finding, not necessarily associated with hyper-
cholesterolemia (BOX 2). Xanthoma (type and site) and Corneal arcus
Blood pressure measurement should be necessarily part (age of first detection)
of cardiovascular assessment of FH patient. Standard elec- Blood Pressure, ECG, Echocardiography, Carotid
trocardiogram (ECG) should be performed to detect signs of ultrasound (intima media thickening, plaque)
suspect myocardial ischemia, although a stress ECG is ex- Instrumental investigations, upon indication of
pected to be more sensitive for ischemia. Carotid ultrasound the cardiologist
investigation has become very popular because of its non- ApoB: apolipoprotein B; DLCN: Dutch Lipid Clinic
invasiveness, relatively low cost and established predictive Network; ECG: electrocardiogram; HDL-C: HDL
power for cardiovascular events. Bilateral carotid scan can cholesterol; LDL-C: LDL-cholesterol; Lp(a): Lipo-
be performed according to a standardized procedure, which protein (a); MI: myocardial infarction; PVD: periph-
allows measurement of intima-media thickening of com- eral vascular disease; TG: triglycerides.
mon carotid arteries (CIMT), bifurcation and internal carotid

arteries. The identification of carotid plaques is critical The Panel suggested that HoFH should be suspected if
(areas of localized thickening >2.0 mm, with loss of paral- untreated LDL-C levels are >10 mmol/L (>w400 mg/dL),
lelism of ultrasound interfaces). The presence of plaque requiring further evaluation, including a detailed medical
calcification suggests relatively stable plaque, while echo- and family history and/or genetic testing.
lucent plaques are those more prone to thrombotic com- Recently published data have confirmed that LDL-C
plications. Echocardiography is part of the cardiologic levels in HoFH patients can overlap with those usually
assessment of FH patient. Aortic valve abnormalities are seen in HeFH. In two studies, patients with genetically
more specifically related to hypercholesterolemia. In gen- confirmed HoFH had untreated LDL-C levels <12.9 mmol/
eral, the extension and severity of cardiovascular damage L (<500 mg/dL) [75] with LDL-C ranging from 4.4 to
are directly related to hypercholesterolemia (severity and 27.2 mmol/L (170e1053 mg/dL). Among the 125 homo-
years of exposure) and to the type of causative pathogenic zygous ADH and 66 ARH patients characterized in Italy
variant: negative allele (null allele) or allele with residual [6], 56 ADH (45%) and 22 ARH (33%) did not meet the
functional activity (defective allele) (see below) [70]. classic diagnostic criteria for HoFH. Furthermore, patients
with genetically confirmed HoFH treated with traditional
6.2. Management lipid-lowering agents may exhibit treated LDL-C levels
<8 mmol/L (<300 mg/dL). Thus, the diagnosis of HoFH
FH patients should undergo at least one visit a year, even if should not be excluded based solely on LDL-C levels but
clinical signs of cardiovascular disease are absent. Symp- must also include other supportive findings such as
tomatic FH patients should be evaluated and followed up family history, early occurrence of ASCVD, lack of
by a clinical cardiologist. Early diagnosis and clinical con- response to cholesterol-lowering treatments or genetic
trol of cardiovascular complications imply communication evidence. Even if there is not genetic evidence for the
and discussion with a cardiologist, who will also give presence of two pathogenic variants, subjects with high
advice on type and frequency of instrumental in- LDL-C in the range of HoFH showing tendon and cuta-
vestigations. Lifestyle (diet, physical exercise, smoking neous xanthomata before the age of 10 years should be
habits) should be monitored. In this regard, non-medical diagnosed as HoFH. It is worth to remember that xan-
support would be of great value, if available. thomas also occur in Sitosterolemia [76], which may be a
The lifestyle counseling including the change of dietary phenocopy of HoFH as well as in Lysosomal Acid Lipase
habits and the implementation of physical activity should be Deficiency, although this latter disorder has other dis-
initiated as early as possible. Clinicians should be aware that tinguishing features.
the LDL-C lowering effects of dietary interventions aimed at All suspected HoFH patients should undergo molecular
reducing the intake of saturated fatty acids and increasing diagnosis, if available. This is crucial to tailor therapeutic
the intake of soluble fiber is relatively modest in patients management (see below) and for cascade screening to
with HeFH. The caloric restriction is useful in reducing body identify additional siblings with HoFH and HeFH.
weight and triglyceride plasma levels. Evidence supporting
the role of the Mediterranean diet in FH are limited but 7.2. Clinical management and proposed screening for
seem to suggest a favorable effect in reducing the LDL-C, ASCVD in HoFH
apoB and C reactive protein levels. Moreover, when sup-
plemented with plant sterols Mediterranean diet may Once a diagnosis of HoFH is suspected, a consultation be-
reduce LDL-C, especially in FH children [71,72]. Limitations tween lipid specialist and patients should be arranged and
in physical exercise and working activity should be dis- the patients should be managed under the long-term su-
cussed with the patient, considering the issue of possible pervision of a lipidologist. At diagnosis, additional car-
rehabilitative interventions. During follow-up visits, drug diovascular risk factors (i.e. blood pressure, weight, diet,
response should be investigated and possible treatment side exercise, smoking and alcohol use) should be assessed and
effects identified and discussed with the patient. re-evaluated at least twice a year together with the eval-
uation of treatment response.
7. Recommendations for diagnosis and clinical HoFH is characterized by accelerated atherosclerosis,
evaluation of homozygous familial typically located at the aortic root and coronary ostia, even
hypercholesterolemia though other vessels (carotid arteries, descending aorta,
and ileo-femoral and renal arteries) may be affected
7.1. Diagnosis of HoFH [77,78]. Therefore, all HoFH patients at diagnosis should be
referred for the assessment of coronary and carotid arterial
Homozygous form of FH is a rare genetic disorder char- disease with full investigation as appropriate (see below).
acterized by severely elevated levels of LDL-C and the Very recently, a large registry (HoFH International
occurrence of premature ASCVD very early in life. It is Clinical Collaborators eHICC) confirmed that the occur-
caused by bi-allelic pathogenic variants [73] affecting key rence of major manifestations of ASCVD or aortic stenosis
proteins in the LDLR pathway [6]. at diagnosis was as high as 36% in patients with HoFH.
According to the 2023 Consensus Panel on FH of the Moreover, one third of patients had supra-valvular aortic
European Atherosclerosis Society (EAS) the diagnosis of stenosis, which frequently required surgical intervention.
HoFH can be made based on genetic or clinical criteria [74]. These results confirm the need of early diagnosis and early

evaluation of subclinical and overt ASCVD in all HoFH The lipid-lowering therapeutic attitude towards preg-
patients immediately after diagnosis. nant FH women must take into account several general
In first place, non-invasive testing for asymptomatic considerations. In the first place, clinician should assess
cardiac ischemia should be considered in HoFH. If avail- the severity of FH and verify the presence of a preexisting
able, computed tomography coronary angiography (CTCA) cardiovascular disease that could be exacerbated during
every 5 years, or more frequently if clinically indicated, pregnancy. Another consideration arises from the fact that
should be considered. Nevertheless, invasive coronary several evidence has reassured on the safety of statins
angiography is indicated in patients with clinical symp- during pregnancy [84]. A statin-based therapy should be
toms suggestive of ischemia or valve disfunction, or in the proposed to selected HoFH or severe HeFH women during
presence of findings of ischemia from non-invasive cardiac pregnancy [85,86] mainly in those women with an estab-
evaluation. Although stress echocardiography may not be lished ASCVD. The discontinuation of statin therapy during
considered as preferred first line test [79], it could be pregnancy should be considered especially for FH women
useful when CTCA is not available or not possible for who have been optimally managed earlier in life, as a
clinical reasons. Aortic valve and aortic root should be continuous, prolonged adherence to lipid-lowering ther-
evaluated by echocardiography at presentation and apy before pregnancy could prevent pregnancy-related
annually. complications such as acute coronary syndrome [80]. At
this regard, HeFH women could be more easily eligible to
8. Diagnosis and clinical management in special FH treatment discontinuation than HoFH women due to less
populations severe phenotypic features of the disease.
In HoFH female during pregnancy lipoprotein apheresis
8.1. FH in fertile women (LA) may be considered as the treatment of choice [85,86].
In view of the well-known changes in volemia during
Three important issues for women with FH need to be pregnancy, the pressure gradient across the aortic valve
addressed: a) contraception; b) pregnancy; c) breastfeeding. and root should be assessed by echocardiography in all
Contraception is recommended for women who are pre-conception HoFH women and monitored during
taking any LDL-C lowering drugs (except for bile acid pregnancy.
sequestrants) employed for FH treatment because their Regarding breastfeeding, lipid-lowering therapies, with
potential teratogenic effect [80]. However, risks and ben- the exception of bile-acid sequestrants, must be dis-
efits of contraception need to be balanced individually. The continued during lactation. No definitive guidelines on the
thrombotic risk associated with hormonal contraceptive management of FH women during breastfeeding are
methods should be carefully assessed and combined for- available, although a duplex management strategy is
mulations, particularly those of third generation should be possible: maintain lactation for breastfeeding deferring FH
avoided [81,82]. Thus, non-hormonal techniques for treatment or resume lipid-lowering therapy giving up
contraception are recommended (namely a non-hormonal breastfeeding. In every case, it is desirable that the deci-
intrauterine device) or if this is not feasible, oral contra- sion should be shared between the woman and the
ceptives with the lowest thrombotic risk should be physician.
selected, preferring progesterone-only based contracep-
tives [80]. 8.2. FH in children
Regarding pregnancy, a preliminary counseling must be
considered as a crucial clinical step for both HoFH and In the pediatric population, FH diagnosis is based on lab-
HeFH women. This counseling should be oriented to in- oratory values, patients’ family history, clinical and genetic
crease the awareness about risks and expectations of criteria (BOX 3). Early identification of FH children repre-
pregnancy, considering also the side effects of lipid- sents a crucial factor to achieve a normal life expectancy,
lowering drugs. Moreover, counseling for women with as well as to diminish risk of early events and mortality
HoFH must include the information that their children will [52,87]. However, the finding of FH-typical clinical mani-
have HeFH and, if their partner has HeFH, the risk of festations represents a critical issue in young HeFH, due to
newborn child with HoFH is 50%. To this regard, the the limited timeframe exposure to high LDL-C levels,
partner of a FH woman should always be tested for FH if leading to delayed cardiovascular involvement. In fact, the
the desire to become pregnant has been expressed. main biochemical and clinical parameters employed in
For these reasons, FH women should be advised that phenotype-based diagnosis, such as elevated LDL-C levels
pregnancy need to be discussed at multidisciplinary level or detection of premature coronary heart disease, tendon
and closely monitored. In fact, pregnancy, particularly in xanthoma, and/or corneal arch, show a poorly clinical
HoFH, is associated with further increase in LDL-C and usefulness in very young children [88]. Xanthomas and
lipid-lowering therapies are usually discontinued with corneal arch are rarely observed in childhood, except from
possible consequences on cardiovascular morbidity and the most severe HoFH forms. Furthermore, LDL-C levels
mortality. If a FH woman is planning to conceive, it is typically display relevant fluctuations, thus hindering the
generally recommended to discontinue statins and eze- identification of cut-offs specific for a timely diagnosis
timibe therapy from one to three months before [88,89]. The diagnosis based upon the DLCN criteria has
conception [83]. not been validated in children and adolescents [90]. In

vegetables, fruits, whole grains, ﬁsh and low-fat products

BOX 3 should be suggested, together with systematic physical
When FH should be suspected in children and what activity.
to do. Children and adolescents with HoFH should receive a
consultation by a pediatric cardiologist for clinical and
instrumental evaluation of the atherosclerosis burden
using non-invasive imaging, such as CTCA and carotid ul-
1.1 If one parent has an ascertained HeFH, all trasonography, as well as exercise testing or functional
of the proband’s seemingly healthy chil- cardiac imaging, as clinically indicated. Non-invasive car-
dren should be addressed to proper diac and vascular imaging techniques may be also used
screening to ascertain/exclude HeFH during follow-up of FH children and adolescents to assess
1.2 In a child with repeated abnormal LDL-C the impact of lipid-lowering treatment.
levels (>3.5 mmol/L; >135 mg/dL) after Prenatal diagnosis on chorionic villi samples is possible,
exclusion of secondary causes of upon family’s specific request, in those cases when the
hypercholesterolemia, causative mutation has been previously identified in both
i) perform clinical and laboratory investi- parents at heterozygous state [91,92].
gation in parents
ii) reconstruct history of ascendents,
9. Imaging techniques for evaluating subclinical
iii) pay attention to the unfrequent sce-
atherosclerosis in HeFH and HoFH patients
nario of a “de novo mutation” if parents
are mutation-negative, or the particular
Patients with FH carry a higher risk of premature ASCVD
case of adopted child
[23,93]. In untreated patients with HoFH, development of
1.3 In children with repeated abnormal LDL-C ASCVD and/or aortic disease (valvular and supravalvular)
levels (>10.3 mmol/L; >400 mg/dL) and is expected as early as in the first decade of life [77]. In fact,
eventual evidence of cutaneous and/or it has been reported that in patients <16 years old, 10%
tendon xantomatosis have clinical ASCVD, 40% subclinical evidence of ASCVD,
i) suspect the presence of HoFH and 40% aortic valve disease (regurgitation or stenosis). In
ii) analyze the biochemical phenotype in those between 16 and 30 years old, 90% show clinical
parents to confirm a dominant trans- ASCVD. Yet, a systematic investigation of the cost effec-
mission (ADH) or recessive trans- tiveness of traditional and advanced cardiovascular imag-
mission (ARH) or phenocopies ing techniques to detect subclinical ASCVD is lacking in
(Sitosterolemia or Lysosomal Acid patients with either HoFH or HeFH, and therefore recom-
Lipase Deficiency). mendations can be made only based on a consensus
iii) perform genetic analysis of the genes agreement. Previous studies [77,94] suggest the utility of
responsible for ADH, ARH, Sitosterolemia the ultrasound of carotid intima-media thickness,
and Lysosomal Acid Lipase Deficiency. computed tomography (CT)-based coronary artery calcium
(CAC) quantification, and magnetic resonance based aortic
atherosclerosis evaluation in vascular assessment in pa-
tients affected by FH. More recently, CTCA has emerged as
the most accurate non-invasive imaging modality to assess
coronary artery atherosclerosis in symptomatic and
presence of elevated LDL-C levels secondary causes should asymptomatic patients. CAC has been shown to be a sur-
be excluded, including hypothyroidism, nephrotic syn- rogate marker for atherosclerosis, with the calcium score
drome, obstructive liver disease, obesity, anorexia nervosa ‘Agatston score’ being proportional to atherosclerosis pla-
or drug-induced dyslipidemia. One way to improve the que burden and cardiovascular risk [93]. However, further
low diagnostic rates of FH in most of European populations prognostic studies are needed to evaluate the value of
consists in implementation of FH screening in childhood. cardiac CT for stratification of subjects who may have a
The FH pediatric screening was recognized by the Euro- baseline risk higher than the general population, such as
pean Commission Public Health Best Practice Portal as one FH patients, and no recommendations about the use of
of the best practices in non-communicable disease pre- advanced non-invasive imaging in asymptomatic FH pa-
vention. Imaging of increased CIMT and abnormal flow- tients are reported in the current guidelines.
mediated dilation have been reported in young HeFH pa- Current guidelines classify HeFH patients without other
tients, and several studies documented an improvement in cardiovascular risk factors at high ASCVD risk and target
these preclinical markers of atherosclerosis upon lipid- LDL-C value to be achieved with therapy is < 70 mg/dL.
lowering treatment. The reduction of LDL-C level is the Patients with HeFH who have at least one other cardio-
main goal of therapy to prevent worsening of ASCVD. vascular risk factor or who have already had a cardiovas-
The pediatric FH patients should be encouraged to cular event or have subclinical atherosclerosis, are at very
maintain adherence to lifestyle modifications even after high cardiovascular risk and the target LDL-C value
pharmacological treatment initiation. A healthy diet rich in is < 55 mg/dL [95,96]. As a consequence, detection of

subclinical atherosclerosis has gained increasing relevance Treatment should be initiated with high-intensity statin
in order to perform accurate ASCVD risk stratification and therapy (atorvastatin 40/80 mg, rosuvastatin 20/40 mg). In
to guide therapy, and should be considered especially in most cases statins should be taken in combination with
asymptomatic HeFH patients with a history of premature ezetimibe [98]. PCSK9 inhibitors (alirocumab [99] and
familial ASCVD events. evolocumab [100]), taken subcutaneously every two
In conclusion, patients with HoFH should be investi- weeks and inclisiran [101] every six months, are recom-
gated at diagnosis, even if asymptomatic, for ASCVD, aortic mended in very-high-risk patients with HeFH when the
valvular disease and aortic supravalvular stenosis using treatment goal is not achieved on maximal tolerated statin
CTCA and echocardiography, whereas functional tests (e.g. plus ezetimibe (BOX 4). PCSK9 inhibitors are also recom-
stress imaging techniques) or preferably anatomic CTCA mended in patients who cannot tolerate statins.
techniques are to be considered for assessing ASCVD in Bempedoic acid is a novel non-statin drug that inhibits
HeFH. Initial Coronary (CT) Angiography is recommended cholesterol biosynthesis in the same pathway as statins
for HoFH as per the EAS recent guidance [74]. [102]. It is administered as a prodrug and is only converted
to active drug in the liver and not muscles. Bempedoic
10. Treatment of familial hypercholesterolemia acid, alone or in combination with ezetimibe and PCSK9
inhibitors, may represent a valid alternative in patients
10.1. Drug treatment of HeFH intolerant to statins.
Bile acid sequestrants (colestiramine [103] and colese-
The aim of the drug therapy of HeFH is to lower LDL-C velam) can be used as third-line agents in patients not at
levels to decrease cardiovascular risk. The greater the ab- target for LDL-C and in those with statin intolerance.
solute LDL-C reduction, the greater the cardiovascular risk However, they are poorly tolerated and have limited effi-
reduction [97]. Treatment goals should be identified after cacy on LDL-C reduction [104].
the assessment of total ASCVD risk. Inclisiran, a small interfering RNA which reduces the
As indicated above, patients with HeFH and ASCVD or intrahepatic expression of PCSK9, is now available for the
with another major risk factor are classified to be at very- treatment of patients not at target for LDL-C [105]. After an
high-risk, and an LDL-C reduction of >50% from baseline initial dose, the drug will be given again subcutaneously
and an LDL-C goal of <1.4 mmol/L (<55 mg/dL) are rec- after three months, and then twice a year.
ommended; <1.0 mmol/L (<40 mg/dL) if the patient High intensity statin treatment may be associated with
experienced a second vascular event within 2 years. Pa- several side effects. In particular muscle adverse events
tients with HeFH without known ASCVD and without (myalgias, muscle weakness, myositis) are the most
other risk factors are classified to be at high-risk, and an commonly reported. However, most statin intolerant pa-
LDL-C reduction of >50% from baseline and an LDL-C goal tients can tolerate them when reinitiated at a later time
of <1.8 mmol/L (<70 mg/dL) are recommended [63]. and possibly with a different statin [106]. True statin-
Cholesterol-lowering medications should be taken intolerant patients can be managed with alternative ther-
regularly and initiated as soon as possible after the diag- apies including bempedoic acid and PCSK9 inhibitors.
nosis of HeFH. Statins in addition to dietary and lifestyle Cholesterol-lowering treatment should be carefully
modifications are the first-line drugs. Other drugs include monitored to improve compliance. Given the very high
ezetimibe, bempedoic acid, PCSK9 inhibitors, bile acids baseline LDL-C plasma levels few patients reach LDL-C
sequestrants and inclisiran. The average LDL-C reduction goals [107]. Patient and physician should regularly reassess
ranges from z30% with moderate intensity statins to tolerance to medication and share benefits of treatment,
z50% with high intensity statins and z85% with associ- and therapeutic plan.
ation therapy with PCSK9 inhibitor plus high intensity
statin plus ezetimibe (Table 4). The intensity of therapy 10.2. Drug treatment of HoFH
should be selected to achieve the recommended
reduction in LDL-C based on the person’s estimated risk of Lifestyle intervention and maximal tolerated dose of a high
ASCVD. efficacy statin plus ezetimibe, are the mainstays of

Table 4 Percent LDL-C reduction with different cholesterol-lowering treatments.

Drug treatment % LDL-C reduction

Moderate intensity statins (atorvastatin 10e20 mg; rosuvastatin 5e10 mg; 30%
simvastatin 20e40 mg; pravastatin 40e80 mg)
High intensity statins (atorvastatin 40e80 mg; rosuvastatin 20e40 mg) 50%
High intensity statins þ ezetimibe 10 mg 65%
PCSK9 inhibitors (alirocumab, evolocumab, subcutaneously every two weeks) 60%
High intensity statins þ PCSK9 inhibitors 75%
High intensity statins þ PCSK9 inhibitors þ ezetimibe 10 mg 80%
Bempedoic acid 180 mg 20%
Bempedoic acid 180 mg þ ezetimibe 10 mg 40%

The management of HoFH has rapidly progressed over

BOX 4
the last decade with the availability of several innovative
Highlights of lipid-lowering treatment of HeFH
drugs.
PCSK9 inhibitors (monoclonal antibodies, PCSK9 mAb)
administered every other week or monthly may be used in
HoFH. The response to PCSK9 inhibitors depends largely
1. Assess total ASCVD risk (high or very high)
on the LDLR residual activity with no or poor effectiveness
2. Identify LDL-C treatment goals (<70/<55/
in those patients carrying two null alleles (LDLR-NEG al-
<40 mg/dL and 50% reduction)
leles) or ARH [119,120]. Overall, these drugs are generally
3. Share the goals, benefits and possible side ef-
safe and are associated with an LDL-C percent reduction
fects of therapy with the patient and involve
up to 30% [100,121,122]. On the other hand, the treatment
him in the therapeutic decision-making process
with inclisiran, a small interfering RNA (siRNA) against
4. Encourage a healthy lifestyle (healthy diet,
PCSK9, did not reduce LDL-C levels in patients with HoFH
smoking cessation, physical activity)
despite substantial lowering of PCSK9 levels [123]. The use
5. Start therapy with high intensity statins
of PCSK9 inhibitors on top of statins and ezetimibe
(atorvastatin 40/80 mg or rosuvastatin 20/
tailoring depends on the molecular diagnosis. If the lipid
40 mg) plus ezetimibe 10 mg
phenotype or molecular diagnosis suggests LDLR-NEG or
6. Add PCSK9 inhibitor (alirocumab or evolo-
ARH, the use of PCSK9 inhibitors will be ineffective.
cumab taken subcutaneously every two
Lomitapide is a small molecule inhibiting the micro-
weeks) if treatment goal is not achieved on
somal triglyceride transfer protein (MTTP) to reduce pro-
maximal tolerated statin plus ezetimibe
duction of very low-density lipoprotein (VLDL) and LDL
7. Regularly reassess tolerance to medication
thus acting independently of LDLR residual activity. Lomi-
and evaluate treatment adherence
tapide inhibits also intestinal MTTP, thereby reducing chy-
8. Discuss the results and give positive feed-
lomicrons and determining fat malabsorption. Results from
backs for successfully reaching the treat-
clinical trials have showed that it reduces LDL-C by 40e70%
ment goals
in HoFH with an acceptable safety and tolerance profile
SCVD: atherosclerotic cardiovascular event;
[124] and therefore, since 2013 lomitapide can be used in
LDL-C: LDL cholesterol.
Italy to treat HoFH [125]. These results have been confirmed
by real world-data [126e130] confirming the efficacy data
and reassuring on the medium-term safety. Despite this, the
treatment [108,109]. Under those circumstances LDL-C major limitations associated with this drug are the high cost
reduction largely depends on the residual LDLR activity and the potential warning on the long-term liver-safety. The
and statins, alone and in combination with ezetimibe, have use of lomitapide in all HoFH as III-line therapy or as II-line
been proved to reduce ASCVD risk in HoFH and should be therapy in LDLR-NEG HoFH and ARH patients is recom-
started at diagnosis [48,110]. mended. This drug should be used with the support of an
Bile acid sequestrants are largely ineffective and are not expert dietician to reduce the side effects associated with
recommend in HoFH [111]. steatorrhea. In agreement with the Italian Medicines
Liver transplant often coupled with heart trans- Agency (AIFA) disposition [131], the liver function as well as
plantation, has been an option to treat HoFH. Most pa- regular screening for steatohepatitis/fibrosis or progressive
tients still require post-transplant lipid-lowering therapies liver disease should be strictly monitored.
and the need of long-term immunosuppressant therapy The angiopoietin-like 3 (ANGPTL3) protein has emerged
[112]. Moreover, progression of aortic valve disease has in the last years as a very attractive therapeutic target
been observed despite the surgical procedure [113]. since homozygous carriers of LOF mutations of ANGPTL3
Therefore, liver transplant should be considered only as are characterized by a marked reduction of ApoB and
last option when conventional or innovative drugs are not ApoA1 containing lipoproteins and reduced ASCVD risk
available. [132e134]. Evinacumab is a monoclonal antibody that in-
Lipoprotein apheresis (LA) is recommended to be star- hibits ANGPTL3 [135] whose use was recently tested in a
ted by age 3 and no later than 8 years. LA is effective in Phase III trial (ELIPSE trial) showing that the infusion of
acutely reducing LDL-C (55e70%) [114] with a mean long- 15 mg/kg of body weight once every 4 weeks was associ-
term reduction ranging from 21% to 36% [115]. Major ated with a 47% reduction of LDL-C independently from
limitations include limited availability worldwide and the background HoFH genotype. No clinically relevant side
costs together with the high impact on social and effects were registered during the trial. Considering the
emotional burden (i.e., educational attainment, employ- outbreaking results of the ELIPSE trial, the use of evina-
ment related issues) in HoFH treated patients [116,117]. cumab was approved for treating HoFH patients from the
Although mitigated, aortic valve stenosis and ASCVD still age of 12 by EMA and FDA, and, more recently from AIFA.
progress in a consistent number of LA treated patients The use of evinacumab is recommended in all HoFH as III-
[118]. Despite this, when available, LA should be offered to line therapy or as II-line therapy in LDLR-NEG HoFH or
HoFH patients, particularly in the pediatric population and ARH patients as an alternative to lomitapide or in combi-
in pregnancy, possibly with a weekly frequency. nation with it. The choice to use lomitapide or evinacumab

Please cite this article as: Tarugi P et al., Consensus document on diagnosis and management of familial hypercholesterolemia from the
Italian Society for the Study of Atherosclerosis (SISA), Nutrition, Metabolism & Cardiovascular Diseases, [Link]
[Link].2024.05.002
Italian consensus document on FH
[Link].2024.05.002
Italian Society for the Study of Atherosclerosis (SISA), Nutrition, Metabolism & Cardiovascular Diseases, [Link]
Please cite this article as: Tarugi P et al., Consensus document on diagnosis and management of familial hypercholesterolemia from the

Table 5 LDL cholesterol-lowering treatments, their efﬁcacy and side effects in HoFH.

Name Mechanism of Administration Dosage LDL-C lowering Adverse event References

action route effect
LDLR dependent Statins Reduction of Oral Variables dosage Variable LDL-C- Myalgia [136,137]
cholesterol daily lowering effect Myopathy
biosynthesis depending on Liver toxicity
through HMG- the residual
CoA reductase LDLR activity
inhibition
[ LDLR activity
Ezetimibe Y Cholesterol Oral 10 mg daily Plus 10%e15% on Liver toxicity [141e143]
absorption top of statins
[ LDLR activity
Alirocumab- Y LDLR Subcutaneous 75/150 mge140 21%e35% Injection site [100,121,122,138
Evolocumab degradation mg bi-monthly reactions e140,144]
(monoclonal Flu like
antibodies) symptoms

LDLR Lomitapide Y Microsomal Oral Variables dosage LDL-C (50%) Hepatic [124,126
independent triglyceride daily ApoB (49%) steatosis e128,130,145e150]
transfer protein Gastrointestinal
activity disorders
Inhibition of LDL Impaired liver
production function
Evinacumab Inhibition of Subcutaneous 15 mg/kg LDL-C (43.4% Flu-like [134,135,151e156]
ANGPTL3 monthly e49.1%) symptoms
[ lipoprotein
lipase activity
Y VLDL secretion
Lipoprotein Physical removal Extracorporeal Weekly or LDL-C (acutely Hypotension [114,115]
Apheresis of LDL by treatment of biweekly 55e70%; long- Iron deﬁciency
selective and whole-blood or term 21e36%) anemia (long-
non-selective plasma Lp(a): acutely 55 term)
methods e70%

13
14 P. Tarugi et al.

may be related to patient preferences (oral vs. intravenous developed. This updated SISA Consensus document pro-
injection) and reimbursement policies especially for vides a pragmatic guidance to improve early diagnosis and
combined treatment as well as the tolerability of the to plan appropriate LDL-C lowering therapies in this con-
treatment. dition. This document is addressed not only to lipidologists
HICC registry data highlighted that HoFH patients that but also to other physicians (i.e. general practitioners, car-
do not receive adequate combination of lipid-lowering diologists, pediatricians) to promote a better care and to
therapies, have higher on-treatment LDL-C levels and improve the cardiovascular health of FH patients.
shorter survival free from cardiovascular events [78]. A
combination of all the available therapeutic tools to achieve
Contribution statement
LDL-C targets in HoFH and reduce the associated cardio-
vascular disease burden is recommended. Table 5 provides
Francesco Angelico, Sebastiano Calandra, Manuela Casula,
an overview of the lipid-lowering therapies available to
Angelo B. Cefalù, Laura D’Erasmo, Giuliana Fortunato,
treat FH categorized in two groups based on the mechanism
Pasquale Perrone-Filardi, Paolo Rubba, Patrizia Suppressa,
of action: LDLR dependent and LDLR independent drugs
equally contributed to the manuscript.
[100,114,115,121e124,126e128,130,134e140,141,143e156].

10.3. Treatment of HeFH and HoFH patients during Funding

pediatric age
This research did not receive any specific grant from
The cornerstone of pharmacotherapy in HeFH children and funding agencies in the public, commercial, or not-for-
adolescents is represented by the use of statins [48] profit sectors.
maximally tolerated/age-appropriate dose [157,158].
Pharmacological treatment in HeFH is approved for the
age 6 years. Pravastatin and rosuvastatin are approved Declaration of competing interest
for use in children aged 8 and 6 years, respectively. As
statin use is contraindicated in pregnancy and lactation, The authors have nothing to disclose.
suitable contraception is necessary to all post-pubertal
young girls on lipid-lowering treatment. A second drug Acknowledgements
to use is ezetimibe, which has been shown to reduce LDL-C
by additionally 15e20%, when added to statins and is well We are very grateful to Dr. Federica Galimberti for her
tolerated. Lipoprotein apheresis is the main recommended expert assistance in the finalization of the manuscript. The
treatment for HoFH children, usually low responders to work of ALC is supported in part by the grant Ricerca
pharmacotherapy. LA should be initiated as soon as Corrente to IRCCS Multimedica by the Italian ministry of
possible, starting even before the age of 8 years (in very Health.
severe cases, as soon as 3 years of age). A single treatment
can lower LDL-C by 55e70%, while the long-term therapy
has proved to result in the regression of xanthomas and References
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Consensus

Uploaded by

Consensus

Uploaded by

Nutrition, Metabolism & Cardiovascular Diseases (xxxx) xxx, xxx

Available online at [Link]

Nutrition, Metabolism & Cardiovascular Diseases

Consensus document on diagnosis and management of familial

1. Introduction the recruitment of the LDLR in clatrin coated pits on the

Genes Chr. Pathogenic Variant type Inheritance Prevalence of gene

Table 2 Aspects relevant to patient diagnosis to be highlighted in the genetic report.

Section Notes Potential implications for physicians/

Genotype-phenotype correlations Clinical consequences

vegetables, fruits, whole grains, ﬁsh and low-fat products

Table 4 Percent LDL-C reduction with different cholesterol-lowering treatments.

Drug treatment % LDL-C reduction

The management of HoFH has rapidly progressed over

Name Mechanism of Administration Dosage LDL-C lowering Adverse event References

10.3. Treatment of HeFH and HoFH patients during Funding

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