Downloaded from
`
`http://eurheartj.oxfordjournals.org/
`
` by guest on June 4, 2016
`
`European Heart Journal (2014) 35, 2146–2157
`doi:10.1093/eurheartj/ehu274
`
`REVIEW
`
`Clinical update
`
`Homozygous familial hypercholesterolaemia: new
`insights and guidance for clinicians to improve
`detection and clinical management. A position
`paper from the Consensus Panel on Familial
`Hypercholesterolaemia of the European
`Atherosclerosis Society
`
`Marina Cuchel*, Eric Bruckert, Henry N. Ginsberg, Frederick J. Raal, Raul D. Santos,
`Robert A. Hegele, Jan Albert Kuivenhoven, Børge G. Nordestgaard,
`Olivier S. Descamps, Elisabeth Steinhagen-Thiessen, Anne Tybjærg-Hansen,
`Gerald F. Watts, Maurizio Averna, Catherine Boileau, Jan Bore´ n, Alberico L. Catapano,
`Joep C. Defesche, G. Kees Hovingh, Steve E. Humphries, Petri T. Kovanen, Luis Masana,
`Pa¨ ivi Pajukanta, Klaus G. Parhofer, Kausik K. Ray, Anton F. H. Stalenhoef, Erik Stroes,
`Marja-Riitta Taskinen, Albert Wiegman, Olov Wiklund, and M. John Chapman,
`for the European Atherosclerosis Society Consensus Panel on Familial
`Hypercholesterolaemia†
`
`Institute for Translational Medicine and Therapeutics, University of Pennsylvania, 8039 Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104, USA
`
`Received 13 March 2014; revised 19 May 2014; accepted 13 June 2014
`
`Aims
`
`Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly ele-
`vated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic car-
`diovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of
`HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the
`European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance
`for the recognition and management of HoFH.
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Methods and
`Early diagnosis of HoFH and prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a
`results
`definitive diagnosis, but if unavailable, markedly elevated LDL-C levels together with cutaneous or tendon xanthomas
`before 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents, are suggestive
`of HoFH. We recommend that patients with suspected HoFH are promptly referred to specialist centres for a compre-
`hensive ACVD evaluation and clinical management. Lifestyle intervention and maximal statin therapy are the mainstays of
`treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying
`
`* Corresponding author. Tel: +1 2157462834, Fax: +1 2156156520, Email: mcuchel@mail.med.upenn.edu
`† Affiliations are listed at the Appendix.
`
`& The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.
`This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/ .0/), which
`4
`permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact
`journals.permissions@oup.com
`
`1 of 14
`
`PENN EX. 2085
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`Downloaded from
`
`http://eurheartj.oxfordjournals.org/
`
` by guest on June 4, 2016
`
`Homozygous familial hypercholesterolaemia
`
`2147
`
`therapy. As patients rarely achieve LDL-C targets, adjunctive lipoprotein apheresis is recommended where available,
`preferably started by age 5 and no later than 8 years. The number of therapeutic approaches has increased following
`approval of lomitapide and mipomersen for HoFH. Given the severity of ACVD, we recommend regular follow-up,
`including Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed
`tomography coronary angiography every 5 years, or less if deemed necessary.
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Conclusion
`This EAS Consensus Panel highlights the need for early identification of HoFH patients, prompt referral to specialized
`centres, and early initiation of appropriate treatment. These recommendations offer guidance for a wide spectrum of
`clinicians who are often the first to identify patients with suspected HoFH.
`- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
`Keywords
`Homozygous familial hypercholesterolaemia † Diagnosis † Genetics † Phenotypic heterogeneity † Statins †
`Ezetimibe † Lipoprotein apheresis † Lomitapide † Mipomersen
`
`Introduction
`
`Homozygous familial hypercholesterolaemia (HoFH) is a rare and
`life-threatening disease originally characterized clinically by plasma
`cholesterol levels .13 mmol/L (.500 mg/dL), extensive xantho-
`mas, and marked premature and progressive atherosclerotic car-
`diovascular disease (ACVD). Studies in cultured fibroblasts from
`these patients showed a severe defect in the ability to bind and
`internalize LDL particles, subsequently shown to be caused by
`mutations in both alleles of the gene encoding the LDL receptor
`(LDLR).1 Recent genetic insights, however, indicate that mutations
`in alleles of other genes, including APOB, PCSK9, and LDLRAP1, may
`be present in some individuals with HoFH.
`Untreated, most patients with markedly elevated LDL-C levels
`develop overt atherosclerosis before the age of 20 years, and gener-
`ally do not survive past 30 years.1 Thus, the primary goals of manage-
`ment are prevention of ACVD by early and comprehensive control of
`hypercholesterolaemia, and early detection of complications, with
`specific focus on ostial occlusion and aortic stenosis.2 Unfortunately,
`HoFH is typically diagnosed when considerable coronary athero-
`sclerosis has already developed, emphasizing the need for optimiza-
`tion of treatment in childhood.
`Recent advances have highlighted the (i) prevalence and (ii) het-
`erogeneity of the genetic defects underlying HoFH and its clinical
`phenotype, which are both more pronounced than originally
`believed. Therefore, this Consensus Panel on Familial Hypercholes-
`terolaemia of the European Atherosclerosis Society (EAS) critically
`reviewed current and emerging data with the aim of providing clinical
`guidance for the recognition and management of HoFH patients.
`These recommendations are directed not only to cardiologists and
`lipid specialists, but also to a wide spectrum of clinicians, including
`primary care physicians, paediatricians, dermatologists, and endocri-
`nologists, who are often the first to see and hopefully refer these
`patients. These recommendations will also be a useful reference
`when decisions are made about provision of healthcare for HoFH.
`
`Prevalence of clinical and
`genetically confirmed homozygous
`familial hypercholesterolaemia
`
`Historically, the frequency of clinical HoFH has been estimated at 1 in
`1 000 000 and for heterozygous FH (HeFH) 1 in 500,1 although
`
`Figure 1 Estimated number of individuals worldwide with homo-
`zygous familial hypercholesterolaemia by the World Health Organ-
`ization region. Estimates are based on historical prevalence data
`(1 in a million with homozygous familial hypercholesterolaemia),
`as well as directly detected estimates of familial hypercholesterol-
`aemia in the Danish general population (≏1/160 000). Data from
`Nordestgaard et al.4
`
`higher frequencies in specific populations, such as French Canadians,
`Afrikaners in South Africa, or Christian Lebanese, have been
`reported due to founder effects.3 However, recent studies in unse-
`lected general populations suggest that the prevalence of HeFH
`based on the Dutch Lipid Clinic Network criteria may be as high
`as 1 in ≏2004 or, for molecularly defined HeFH, 1 in 244.5 Conse-
`quently, HoFH may affect as many as 1 in 160 000 – 300 000
`people (Figure 1).
`
`Genetics of homozygous familial
`hypercholesterolaemia
`
`The proteins known to affect LDL receptor function and their role are
`summarized in Figure 2. Most patients with genetically confirmed HoFH
`have two mutant alleles of the LDLR gene (MIM 606945) and their
`parents each have HeFH. Recently, mutations in alleles of three other
`genes were identified as causal in some cases with a severe phenotype
`resembling HoFH. These secondary genes are APOB (MIM 107730) en-
`coding apolipoprotein (apo) B, PCSK9 (MIM 607786) encoding pro-
`protein convertase subtilisin/kexin type 9 (PCSK9), and LDLRAP1
`(MIM 695747) encoding LDL receptor adapter protein 1, which
`uniquely causes a recessive phenotype, since carrier parents have
`lipid profiles.6 Patients are homozygotes, with the same
`normal
`
`2 of 14
`
`PENN EX. 2085
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`Downloaded from
`
`http://eurheartj.oxfordjournals.org/
`
` by guest on June 4, 2016
`
`2148
`
`M. Cuchel et al.
`
`Figure 2 Proteins affecting low-density lipoprotein receptor function. (A) (1) Newly synthesized low-density lipoprotein receptor (LDLR) is
`transported to the cell membrane. After reaching the cell surface, the low-density lipoprotein receptor binds apolipoprotein B-100 (apoB-100),
`the main protein on LDL, forming a complex. (2) The low-density lipoprotein receptor– low-density lipoprotein complex, located in a clarithin-
`coated pit, is endocytosed via interactions that involve the low-density lipoprotein receptor Adaptor Protein 1 (LDLRAP1). (3) Inside the endosome,
`the complex dissociates: apoB-100 and lipids are targeted to the lysosome and degraded, the low-density lipoprotein receptor recycles to the cell
`membrane. (4) Pro-protein convertase subtilisin/kexin type 9 (PCSK9) acts as a post-transcriptional low-density lipoprotein receptor inhibitor and
`through an interaction with it, targets the low-density lipoprotein receptor for degradation,
`instead of recycling. (B) In the presence of
`loss-of-function mutations in the gene encoding for the low-density lipoprotein receptor, the low-density lipoprotein receptor is either not synthe-
`sized, not transported to the surface, or is present on the surface, but its function is altered. (C) In the presence of mutations in the low-density
`lipoprotein receptor-binding region of apoB, its ability to bind to low-density lipoprotein receptor is reduced, with consequent reduction in
`low-density lipoprotein particle uptake. (D) In the presence of gain-of-function mutations in the gene encoding PCSK9, more low-density lipoprotein
`receptors are targeted for degradation, with consequent reduction in the number of low-density lipoprotein receptors which recycle to the cell
`surface. (E). In the presence of loss-of-function mutations in the gene encoding for LDLRAP1, which facilitates the interaction between the low-
`density lipoprotein receptor and the cell machinery regulating the endocytic process, low-density lipoprotein receptor – low-density lipoprotein
`complex internalization is impaired.
`
`3 of 14
`
`PENN EX. 2085
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`Downloaded from
`
`http://eurheartj.oxfordjournals.org/
`
` by guest on June 4, 2016
`
`Homozygous familial hypercholesterolaemia
`
`2149
`
`on in vitro assays in their cultured fibroblasts, patients with clinically
`defined HoFH have been conventionally classified as either receptor-
`negative (,2% residual activity) or receptor-defective (2 – 25%
`residual activity).1 Homozygous familial hypercholesterolaemia
`patients who are LDLR-negative have higher LDL-C levels and
`poorer clinical prognosis than LDLR-defective patients.2,7,8
`Residual LDL receptor activity has not been systematically evalu-
`ated in patients carrying mutations in APOB and PCSK9 genes. In
`patients carrying LDLRAP1 mutations, LDL receptor activity in fibro-
`blast culture is normal, although the cause remains unclear.6 Never-
`theless, emerging data suggest that carriers of mutations in these
`genes may present a milder phenotype compared with that of
`receptor-negative subjects.6 Overall, mean LDL-C levels by genotype
`generally increase as follows: HeFH,double heterozygote (e.g.
`LDLR+PCSK9 gain-of-function or APOB mutation) ,homozygous
`APOB or PCSK9 gain-of-function mutation ,homozygous LDLRAP1
`or LDLR-defective mutations ,compound heterozygote LDLR-
`defective+LDLR-negative mutations ,homozygous LDLR-negative
`mutations (see Supplementary material online and Figure 4).
`Other sources of variability in the HoFH phenotype may arise
`from small effect genetic variants (common single nucleotide
`polymorphisms), gene – gene and gene – environment interac-
`tions, and non-Mendelian and epigenetic influences.6,9,10 Greater
`access and wider clinical application of next generation sequencing
`are critical to defining such variability, as well as additional causa-
`tive genes, all of which have important prognostic and therapeutic
`implications.
`
`Metabolic characteristics of
`homozygous familial
`hypercholesterolaemia
`
`Impaired functionality of the LDL receptor underlies the hyperchol-
`esterolaemia of HoFH. While defective hepatic LDL uptake is the
`main and most direct consequence, other metabolic perturbations
`may contribute to the metabolic characteristics and accelerated ath-
`erosclerotic disease associated with HoFH. ApoB metabolism in
`HoFH remains incompletely defined, although in vitro and in vivo
`studies suggest that LDLR-negative mutations are associated with
`hepatic oversecretion of apoB. In addition, while levels of triglycer-
`ides are frequently within the normal range, hypertriglyceridaemia
`has been observed, and may be more common with an increasing
`prevalence of the metabolic syndrome. Decreased catabolism of
`triglyceride-rich lipoproteins may result from deficient LDL receptor
`function and account for postprandial dyslipidaemia. Familial hyper-
`cholesterolaemia is also associated with increased plasma levels of
`lipoprotein(a) [Lp(a)] by an undefined mechanism that may not dir-
`ectly involve the LDL receptor pathway. Lipoprotein(a) levels tend
`to be higher in HoFH than HeFH, and are independent of genetic vari-
`ation in apolipoprotein(a).4 Finally, HoFH patients frequently have
`low levels of high-density lipoprotein cholesterol (HDL-C), probably
`due to accelerated turnover of HDL apoA-I, and defective
`HDL-driven cholesterol efflux. These metabolic perturbations
`have been extensively reviewed.11
`
`Figure 3 Genetics and genetic heterogeneity of homozygous fa-
`milial hypercholesterolaemia. (A) Inheritance of homozygous famil-
`ial hypercholesterolaemia in a pedigree.
`In a mating between
`heterozygous parents who each carry one copy of a familial
`hypercholesterolaemia-mutation-bearing allele, 25% of children
`will carry two copies of wild-type alleles (homozygous normal);
`50% will be heterozygotes; and 25% will carry two copies of familial
`hypercholesterolaemia-mutation-bearing alleles (homozygous fa-
`milial hypercholesterolaemia). The particular genes and mutation
`types inherited determine whether the affected individual
`is a
`simple homozygote, or compound or double heterozygote. (B)
`Genetic heterogeneity of
`familial hypercholesterolaemia.
`Ideo-
`grams for chromosomes 1, 2, and 19 indicate the positions of the
`four main familial hypercholesterolaemia-causing genes, which in
`the descending order of frequency are LDLR (.95%), APOB (2 –
`5%), PCSK9 (,1%), and LDLRAP1 (,1%). For the vast majority of
`homozygous familial hypercholesterolaemia patients represented
`in (A), mutation-causing alleles are within the same gene (usually
`LDLR) and patients are referred to as ‘true homozygotes’. Homozy-
`gous familial hypercholesterolaemia patients who carry the same
`mutation on each allele are called ‘simple homozygotes’, while
`those who inherit different mutations from within the same gene
`are called ‘compound heterozygotes’. Finally, very rare homozy-
`gous familial hypercholesterolaemia patients have familial hyper-
`cholesterolaemia mutation-bearing alleles from two different
`familial hypercholesterolaemia loci: the first is almost always
`within the LDLR, while the second is from one of the other three
`loci. Such patients are called ‘double heterozygotes’.
`
`mutation in both alleles of the same gene, or more commonly, com-
`pound heterozygotes with different mutations in each allele of the
`same gene, or double heterozygotes with mutations in two different
`genes affecting LDL receptor function (Figure 3).
`
`Genetic heterogeneity translates
`to phenotypic variability
`Irrespective of the underlying genetic defect, the severity of the
`HoFH phenotype depends on residual LDL receptor activity. Based
`
`4 of 14
`
`PENN EX. 2085
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`Downloaded from
`
`http://eurheartj.oxfordjournals.org/
`
` by guest on June 4, 2016
`
`2150
`
`M. Cuchel et al.
`
`Figure 4 Phenotypic variability in homozygous familial hypercholesterolaemia. For full explanation and relevant literature refer to Supplementary
`material online. LDL, low-density lipoprotein; APOB, apolipoprotein B; PCSK9, pro-protein convertase subtilisin/kexin type 9; LDLRAP1, LDL re-
`ceptor adaptor protein 1 (i.e. ARH, autosomal recessive hypercholesterolaemia).
`
`Diagnosis of homozygous familial
`hypercholesterolaemia
`
`Diagnosis of HoFH can be made on the basis of genetic or clinical cri-
`teria (Box 1). While genetic testing may provide a definitive diagnosis
`of HoFH, it is recognized that in some patients genetic confirmation
`remains elusive, despite exhaustive investigation; indeed, the exist-
`ence of additional FH genes cannot be excluded.4 Historically,
`HoFH has been most commonly diagnosed on the basis of an untreat-
`ed LDL-C plasma concentration .13 mmol/L (.500 mg/dL), or a
`treated LDL-C concentration of ≥8 mmol/L (≥300 mg/dL), and
`the presence of cutaneous or tendon xanthomas before the age of
`10 years, or the presence of untreated elevated LDL-C levels consist-
`ent with HeFH in both parents.
`
`Plasma low-density lipoprotein
`cholesterol levels
`Within a family, the plasma LDL-C level is the critical discriminator,
`being about four times and about two times higher in family
`members with HoFH or HeFH, respectively, compared with un-
`affected members.6 At the population level, however, the range of
`LDL-C levels may overlap significantly between HeFH and HoFH
`(Figure 4), and untreated LDL-C levels ,13 mmol/L (,500 mg/dL)
`can be found in genetically confirmed HoFH.5,8 This is especially rele-
`vant for children, who tend to have lower LDL-C levels than adults.
`More than 50% of HoFH children identified in the Netherlands
`have LDL-C levels between 5.6 and 9.8 mmol/L (A Wiegman personal
`communication). Such phenotypic heterogeneity can be at least partly
`explained by the previously described genotypic heterogeneity.
`Thus, the LDL-C cut-offs given here should not be the sole guide
`for diagnosis. Indeed, the treated LDL-C cut-off of .8 mmol/L
`(.300 mg/dL) is now considered obsolete, given the multiplicity of
`
`Box 1 Criteria for the diagnosis of homozygous familial
`hypercholesterolaemia
`
`† Genetic confirmation of two mutant alleles at the LDLR, APOB, PCSK9,
`or LDLRAP1 gene locus
`
`OR
`
`† An untreated LDL-C .13 mmol/L (500 mg/dL) or treated LDL-C
`≥8 mmol/L (300 mg/dL)* together with either:
`
`W Cutaneous or tendon xanthoma before age 10 years
`
`or
`
`W Untreated elevated LDL-C levels consistent with heterozygous FH in
`both parents
`
`* These LDL-C levels are only indicative, and lower levels, especially in
`children or in treated patients, do not exclude HoFH
`
`lipid-lowering treatments that these patients typically receive. This
`point is clearly illustrated in a recent trial, in which HoFH patients
`with a confirmed genetic diagnosis had baseline LDL-C levels as
`low as 3.9 mmol/L (≏150 mg/dL) while on multiple LDL-C lowering
`agents,12 as well as in a recent report.5
`
`Xanthomas and arcus corneae
`Although not exclusively associated with HoFH, the presence of cu-
`taneous or tuberous xanthomas in children is highly suggestive of
`diagnosis (Figure 5). Evidence of arcus corneae reinforces the clinical
`diagnosis. As seen for LDL-C levels, variability in the age at appear-
`ance and extension of xanthomas can be partly explained by the
`underlying mutations, with earlier appearance of xanthomas asso-
`ciated with receptor-negative vs. receptor-defective status.2,8 Chol-
`esterol deposits in the tendons and joints may lead to tendinitis and
`joint pain, which impairs the quality of life of patients, and these may
`
`5 of 14
`
`PENN EX. 2085
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`Downloaded from
`
`http://eurheartj.oxfordjournals.org/
`
` by guest on June 4, 2016
`
`Homozygous familial hypercholesterolaemia
`
`2151
`
`in a recent report.19 Similar to autosomal recessive hypercholester-
`olaemia, sitosterolaemia has an autosomal recessive pattern of
`inheritance and consequently parents may present with normal
`cholesterol levels. Two major features differentiate sitosterolaemia
`from HoFH: (i) markedly (.30-fold) increased plasma concentra-
`tions of plant sterols,18 and (ii) elevated cholesterol levels, which
`respond well to diet and bile acid sequestrants or ezetimibe and
`may not persist after the first two decades of life.18,19 Diagnosis is
`confirmed by genetic analysis, with mutations in two ATP binding
`cassette transporter genes, ABCG5 and/or ABCG8, shown to be
`causative for sitosterolaemia.18
`In summary, this Consensus Panel recommends that diagnosis is
`made by careful assessment of the clinical characteristics and family
`history, as well as genetic testing when the clinical diagnosis of
`HoFH is uncertain or to facilitate ‘reverse’ cascade screening.
`‘Reverse’ cascade screening is in any case strongly recommended.
`
`Cardiovascular complications and
`natural history
`
`The burden of markedly elevated plasma LDL-C levels from birth
`underlies the sequelae of ACVD complications unique to HoFH.4
`The cholesterol-year score, an integrated measure of the severity
`and the duration of hypercholesterolaemia, is directly associated
`with cholesterol deposition in vascular and extravascular compart-
`ments in HoFH patients,20 thus reinforcing the concept that absolute
`LDL-C levels affect the severity of the CV phenotype. In clinically
`diagnosed HoFH, the first major CV events often occur during ado-
`lescence,2,21,22 although angina pectoris, myocardial infarction and
`death have been reported in early childhood, typically in individuals
`who are LDLR-negative.1,2,14 – 16,21 Untreated HoFH patients who
`are LDLR-negative rarely survive beyond the second decade. While
`HoFH patients who are LDLR-defective have a better prognosis,
`almost all develop clinically significant ACVD by age of 30. Long-term
`studies are still needed to assess CV risk in genetically confirmed
`HoFH without the severe phenotype usually observed in clinically
`defined HoFH.
`Homozygous familial hypercholesterolaemia is characterized by
`accelerated atherosclerosis, typically affecting the aortic root, com-
`promising the coronary ostia, but also other territories, including
`the carotid, descending aorta, and ileo-femoral and renal arteries.1,23
`Cholesterol and calcium deposits, as well as fibrosis and inflammation
`in both the aortic root and aortic valve cusps, can lead to supra-
`valvular aortic stenosis (Figure 6).1,24 These manifestations often
`occur within the first and second decades of life.1,2,21,23 Patients
`may be initially asymptomatic, presenting only with cutaneous and
`tendinous xanthomas and possibly, a cardiac murmur in the aortic
`area.2,25 Early involvement of the ascending and descending thoracic
`aorta is frequently observed,1 accompanied by premature severe
`aortic calcification in adult patients.26 Cholesterol deposition on
`valve leaflets may also cause mitral regurgitation.1
`Importantly, valvular and supra-valvular aortic diseases may pro-
`gress even when cholesterol levels are reduced, as a result of haemo-
`dynamic stress and progressive fibrosis over affected territories.24
`Dyspnoea, diastolic and systolic left ventricle heart failure, and
`sudden cardiac death are also common.1,23 In young children, the
`
`Figure 5 Cutaneous and tuberous xanthomas in homozygous fa-
`milial hypercholesterolaemia. Interdigital xanthomas (see B, yellow
`arrows) in children are highly suggestive of homozygous familial
`hypercholesterolaemia diagnosis. Photograph (A) kindly provided
`by Prof. Eric Bruckert. Photograph (B) kindly supplied by Prof. Fred-
`erick Raal.
`
`require surgical removal. In rare cases, patients may present with
`giant ectopic cholesterol xanthomas in the brain, mediastinum, and
`muscles of the buttock.13 As referral following the appearance of
`xanthomas in young children is frequently the key driver of HoFH
`diagnosis,2,14 – 16 prompt recognition is crucial to early diagnosis.
`The presence of markedly elevated LDL-C levels and the absence
`of neurological, cognitive, and ophthalmic symptoms in patients
`with HoFH distinguish them from patients with cerebrotendinous
`xanthomatosis.17
`
`Family history
`A careful family history is essential for comprehensive assessment of
`possible FH in general, and HoFH in particular.4 In the case of auto-
`somal dominant mutations (in LDLR, PCSK9, and APOB genes), both
`parents are obligate heterozygotes and therefore display elevated
`LDL-C levels (frequently .95th percentile by country-specific age
`and gender criteria) and a strong positive family history of premature
`ACVD (,55 years in men and ,60 years in women among first-
`degree relatives). In the case of autosomal recessive hypercholester-
`olaemia (due to LDLRAP1 mutations), parents may exhibit LDL-C
`levels in the normal range, and determination of an extended family
`pedigree may reveal an autosomal recessive pattern of inheritance.
`Systematic cascade or opportunistic screening offers prospective
`parents with HeFH the possibility of making informed decisions pre-
`natally, and identifying HoFH patients at birth, thereby allowing for
`early initiation of treatment. Identification of HoFH can also guide
`‘reverse’ cascade screening for parents and relatives to identify
`patients with FH.
`
`Differentiation from sitosterolaemia
`Although in most cases the diagnosis of HoFH is relatively straight-
`forward, another disorder of
`lipid metabolism, sitosterolaemia
`(alternatively termed ‘phytosterolaemia’), may have a very similar
`clinical presentation, with the presence of tendinous and/or tuber-
`ous xanthomas in childhood associated with a dramatic increase
`in plasma cholesterol and atherosclerotic complications.18 It is,
`however, of relevance that atherosclerotic disease is not always
`present in genetically defined sitosterolaemic subjects, as shown
`
`6 of 14
`
`PENN EX. 2085
`CFAD V. UPENN
`IPR2015-01836
`
`

`
`Downloaded from
`
`http://eurheartj.oxfordjournals.org/
`
` by guest on June 4, 2016
`
`2152
`
`M. Cuchel et al.
`
`frequently if clinically indicated, taking into account the radiation ex-
`posure and severity of subclinical disease. Computed tomography
`coronary angiography can detect luminal obstruction by calcified
`and non-calcified plaques27 and results can be combined with
`those from myocardial stress testing, provided the age of the child
`permits consent. Stress testing, although not optimal for detecting
`subclinical disease, may be used in case of limited access to CTCA
`or cardiac magnetic resonance imaging (MRI). Owing to concerns
`about the exposure of young individuals to radiation, CTCA must
`be performed in CT scanners with at least 64 and preferably 320
`detectors or dual source scanners, with radiation exposure adapted
`for body weight.28 The atherosclerotic burden of the aorta can be
`also evaluated by MRI29 or trans-oesophageal echocardiography.30
`Stress testing and invasive coronary angiography are indicated in
`patients with clinical symptoms suggestive of ischaemia or valve mal-
`function, or in the presence of findings from non-invasive cardiac
`evaluation. Given the high rate of ostial stenosis, risk of sudden
`death and inability to undertake stress testing due to age, invasive
`angiography may be indicated in severely affected young children.
`This should be performed by an experienced paediatric invasive
`cardiologist. Coronary revascularization is indicated for severe
`CHD, and aortic valve replacement for severe left ventricle
`outflow obstruction. For either surgery, care must be taken with
`the aortic root as it is usually severely compromised by atheroscler-
`otic plaques and calcification. Reconstruction of the aortic root might
`be necessary with aortic valve replacement.31 These patients
`should be followed by a team of experts including a lipidologist
`and cardiologist working in close collaboration to optimize thera-
`peutic measures, including pharmacological antiplatelet treatment,
`prevention of endocarditis especially in those with valve prosthesis
`or aortic grafts, and surgical intervention to correct valvular and cor-
`onary impairment.
`
`Current treatment for
`homozygous familial
`hypercholesterolaemia
`
`Given the ACVD complications associated with HoFH, reducing the
`burden of elevated LDL-C levels is critical. A low-saturated fat, low-
`cholesterol, heart-healthy diet should be encouraged in all patients
`with HoFH, but even with strict adherence, diet has little impact on
`the severity of hypercholesterolaemia. Patients should be encour-
`aged to be active. As aortic stenosis may precipitate angina and
`syncope on exertion, a careful assessment of the aortic and ostial in-
`volvement is recommended before sport activities are initiated.
`While other risk factors such as smoking, hypertension, and diabetes
`should be aggressively targeted, and aspirin is of value in asymptom-
`atic patients, the most important aim of therapy is to reduce LDL-C
`levels as much as possible.
`
`Pharmacotherapy
`This Consensus Panel strongly recommends that lipid-lowering
`therapy should be started as early as possible, based on evidence
`that treatment can delay the onset of clinically evident ACVD.2,21
`In accordance with recently published guidelines,4 LDL-C targets in
`HoFH are ,2.5 mmol/L (,100 mg/dL) [,3.5 mmol/L (,135 mg/dL)
`
`Figure 6 Postero-lateral view of computed tomography angiog-
`raphy of a homozygous familial hypercholesterolaemia patient. The
`arrows indicate (1) calcified (in white) and non-calcified (in yellow)
`atherosclerotic plaques in the supra-aortic valve region; (2) calcified
`plaques on the aortic valve region (depicted in green); (3) calcified
`and non-calcified plaques in the ascending aorta; and (4 and 5) cal-
`cified, non-calcified and mixed plaques in the middle and distal right
`coronary artery. Image kindly provided by Prof. Raul D. Santos.
`
`Box 2 Cardiovascular complications of homozygous
`familial hypercholesterolaemia
`
`† HoFH is characterized by accelerated atherosclerosis, typically
`affecting the aortic root, although other vascular territories may also
`be affected.
`† The first major cardiovascular events often occur during
`adolescence, possibly younger when patients are LDLR-negative and/
`or untreated.
`† In young children, early symptoms and signs are often linked to aortic
`stenosis and regurgitation, due to massive accumulation of
`cholesterol at the valvular levels.
`† As aortic and supra-valvular aortic valve diseases may progress even
`when cholesterol levels are reduced, regular screening for subclinical
`aortic, carotid, and coronary heart disease is indicated.
`
`first symptoms and signs are frequently linked to aortic stenosis and
`regurgitation.2 Angina pectoris, resulting from both reduced oxygen
`supply caused by coronary atherosclerosis and increased left ven-
`tricular demand consequent to left ventricle hypertrophy and left
`ventricular outflow obstruction, can occur at any age, depending
`on the rate of progression and severity of phenotype (Box 2).
`
`Screening for subclinical atherosclerosis
`Given the extremely high risk of early onset of severe ACVD and its
`rapid progression in HoFH, regular screening for subclinical aortic
`and coronary heart disease (CHD) is indicated. This Consensus
`Panel recommends that patients receive a comprehensive CV
`evaluation at diagnosis, with subsequent Doppler echocardiograp