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

Abstract

Aims: Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular 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 results: Early diagnosis of HoFH and prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a 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 comprehensive 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 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: Diagnosis; Ezetimibe; Genetics; Homozygous familial hypercholesterolaemia; Lipoprotein apheresis; Lomitapide; Mipomersen; Phenotypic heterogeneity; Statins.

Figure 1

Estimated number of individuals worldwide with homozygous familial hypercholesterolaemia by the World Health Organization region. Estimates are based on historical prevalence data (1 in a million with homozygous familial hypercholesterolaemia), as well as directly detected estimates of familial hypercholesterolaemia in the Danish general population (∼1/160 000). Data from Nordestgaard 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 synthesized, 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.

Figure 3

Genetics and genetic heterogeneity of homozygous familial hypercholesterolaemia. (A) Inheritance of homozygous familial 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 familial 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. Ideograms 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’. Homozygous 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 homozygous familial hypercholesterolaemia patients have familial hypercholesterolaemia 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’.

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 receptor adaptor protein 1 (i.e. ARH, autosomal recessive hypercholesterolaemia).

Figure 5

Cutaneous and tuberous xanthomas in homozygous familial 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. Frederick Raal.

Figure 6

Postero-lateral view of computed tomography angiography 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) calcified, non-calcified and mixed plaques in the middle and distal right coronary artery. Image kindly provided by Prof. Raul D. Santos.

Figure 7

Cumulative low-density lipoprotein cholesterol-lowering effects of statin, ezetimibe, adjunctive mipomersen, lomitapide or evolocumab, and lipoprotein apheresis in homozygous familial hypercholesterolaemia. The per cent low-density lipoprotein cholesterol reduction is dependent on baseline low-density lipoprotein cholesterol values. *The figure illustrates the decrease in low-density lipoprotein cholesterol after a single apheresis treatment. The low-density lipoprotein cholesterol level achieved after treatment is higher in patients with higher baseline value. However, the rebound curves after treatment are more or less parallel. See Schuff-Werner et al.

Figure 8

Case study showing before (A) and 4 years after starting weekly lipoprotein apheresis (B) in a homozygous familial hypercholesterolaemia patient carrying a non-sense mutation in the ARH gene. The patient presented in early childhood with extensive xanthomas on the knees (right knee shown), elbows, buttocks and the Achilles tendon, and elevated total and low-density lipoprotein cholesterol levels [21.9 mmol/L or ∼850 mg/dL; lipoprotein(a) 75 mg/dL]. After 4 years on treatment (statin, ezetimibe plus lipoprotein apheresis), there was total regression of the xanthomas of the knees, buttocks, and elbows. Low-density lipoprotein cholesterol levels at last report were 5.7 mmol/L (∼220 mg/dL) and 1.8 mmol/L (70 mg/dL) before and after apheresis; lipoprotein(a) levels were 50 and 16 mg/dL, respectively. Photographs kindly provided by Prof. Elisabeth Steinhagen-Thiessen.

Figure 9

Novel lipid-regulating drug targets. Novel drugs target either very low-density lipoprotein production (VLDL), by inhibiting apolipoprotein B synthesis (apolipoprotein B [apo B] antisense oligonucleotide, mipomersen) or lipid loading onto nascent apoB [microsomal triglyceride transfer protein (MTP) inhibitor, lomitapide], or low-density lipoprotein catabolism by increasing low-density lipoprotein receptor recycling (PCSK9 inhibitors).

Figure 10

Suggested algorithm for management of homozygous familial hypercholesterolaemia.