A 20-Year Follow-Up Study of Patients Who Have Been Diagnosed with Familial Hypercholesterolemia in Their Youth

Familial Hypercholesterolemia (FH) is a common autosomal co-dominant inherited metabolic disorder characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) [1]. Over time, LDL-C accumulates in the intima-media of arteries and forms atherosclerotic plaques [2]. Therefore, affected individuals with this disorder have a significantly higher risk for early Cardiovascular Diseases (CVD) [3]. The prevalence for Heterozygous FH (heFH) is estimated to be between 1:200 and 1:330 [4,5], while the prevalence of Homozygous FH (hoFH) is estimated to be between 1:160.000 and 1:300.000 [6,7]. Despite the unanimous consensus that initiation of treatment as early as possible reduces cardiovascular risk for patients significantly [8], FH still remains severely underdiagnosed and undertreated. Approximately 90 percent of the affected individuals are not diagnosed and therefore live without treatment [3,9].

FH is caused by mutations in genes encoding for proteins in the catabolism of LDL-C. The LDL-Receptor (LDLR) genes are most frequently affected, followed by the Apolipoprotein B (APOB) genes, the Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) genes and the LDL-receptor-adapter-protein 1 (LDLRAP1) genes [10]. The severity of FH is dependent on to the mutation and the zygosity [11]. Subjects that inherit two mutated alleles suffer from homozygous FH which causes the most severe phenotype leading to a live expectancy of only about 30 years [12]. The clinical manifestation of FH is heterogenous, even though individuals affected by FH start do develop atherosclerosis in childhood and adolescence clinical symptoms mostly do not arise until severe atherosclerosis has formed [6,13,14]. There are cutaneous manifestations of FH such as xanthomata, xanthelasmata, arcus cornealis and tendon xanthomata, which are cholesterol deposits in different tissues of the body [15]. The therapy of FH consists of three main approaches. First, lifestyle intervention including a low-fat diet, physical activity and nicotine abstinence. Second, pharmacological therapy, with Statins, Ezetimibe or PCSK9 inhibitors [12,16]. Statin therapy has been proven to be a safe and effective treatment for children with elevated LDL-C levels and FH [17,18]. Third, invasive therapy such as LDL apheresis, this procedure is primarily reserved for individuals with hoFH or with severe heFH who do not respond adequately to other treatments [12,16]. While there is a universal agreement about the significance and impact of early treatment for FH, there remains a lack of long-term outcome data for patients diagnosed with FH during their childhood or adolescence. Only a limited number of studies have been conducted on this subject. In this paper, detailed data of 13 patients diagnosed with FH in their childhood and adolescence, on average 20 years ago, will be presented and analyzed.

Data was collected from 13 FH patients, who were diagnosed in a pediatric practice during their childhood or adolescence. Informed consent has been obtained from all subjects and/or legal guardians. All experimental protocols were approved by a named institutional committee. On average the included patients have been diagnosed 20 years ago (range 9 to 31 years).

The parameters investigated are:

A. Family history:

1+ Diagnosed familial Hypercholesterolemia in a family member
2+ Myocardial infarction (MCI) and elevated cholesterol levels in a family member
3+ MCI at an early age (<50 years old) in a family member
B. Initial LDL-C at diagnosis, latest LDL-C, FH related DNA mutations, Lipid lowering therapy, IMT of the carotid artery, Years since FH diagnosis, Compliance

Not all the patients regularly underwent a measurement of their IMT, even though all of them were advised to do so. Some of the patients had their IMT measured at diagnosis but not regularly enough to be included in this study. Therefore, the progression of carotid IMT was only reported for the patients who had their carotid IMT measured at diagnosis, regularly afterwards and recently.

The compliance was described as good, moderate, and not compliant by their physicians. To analyze the data differences in LDL-C since diagnosis in percent, the mean initial LDL-C, the mean latest LDL-C, as well as the mean difference in LDL-C levels from diagnosis to now have been calculated.

In Table 1 the results of the analysis of the collected data are presented. It shows the patients family history, age of diagnosis, initial LDL-C, latest LDL-C, LDL-C reduction, DNA-Mutation, treatment, years since diagnosis and age at diagnosis. All 13 individuals have a positive family history for FH. The mean initial LDL-C at diagnosis was 277mg/dl, ranging from 494mg/dl to 173mg/dl. The mean latest LDL-C was 112mg/dl, ranging from 208mg/dl to 70mg/dl. This represents a mean reduction of LDL-C of 59,6% from diagnosis until the end of observation. None of the patients have experienced cardiovascular events up to this point. All included patients are taking Rosuvastatin, a high potent statin, to lower their LDL-C levels. No adverse effects of drug treatment had been reported by the treated subjects. All 13 subjects are described to have a good [11] or moderate [2] compliance by their physician. 12 of the 13 patients have genetically confirmed mutations causing their FH. Out of the 13 subjects, six underwent regular measurements of their Carotid Intima-Media Thickness (cIMT). Among these individuals, two did not exhibit any progression in their cIMT, while four subjects showed an observed progression of their cIMT.

Table 1:Follow-up data.

The present study clearly shows the success and feasibility of long-term treatment of FH- patients, who have been diagnosed in their childhood or adolescence.13 patients have been followed up for at least 8 and up to 30 years, a reduction of LDL-C could be observed in those who remained on the treatment with statins, all of them received rosuvastatin as a treatment. None of the patients had any symptoms of premature atherosclerosis or any manifestation of cardiovascular diseases. No major side effects of the statin therapy have been reported. In those patients who had a repeated measurement of their carotid IMT no major progression of atherosclerosis could be found. Nevertheless, it must be stated, that not even half the patients underwent these measurements regularly. As this highlights the challenge of adherence to therapy and regular diagnostic measurements in the management of people affected by FH it has been decided to publish the data even though they are not complete.

These findings are similar to those of Luirink et al. [19] who reported a mean LDL-C drop of 32% and a mean difference in progression of the IMT by 0,0001mm a year between patients and their unaffected siblings in their 20-year follow-up study of 184 FH patients [19]. Carreau et al. [20] recorded a mean LDL-C reduction between 21-24% in their observational study using medical files of 185 young FH patients treated with pravastatin in two French centers in 2011. Their follow up period ranged from three months to seven years, with a mean duration of two years and two months. Dropouts were not recorded in this study [20]. Elis et al. [21] reviewed the records of 89 FH patients at the Chol. Treatment Center in Cincinnati in 2014. Their analysis even showed a mean decrease in LDL-C levels of 43% under lipid lowering therapy. The mean follow up period in this study is 13±8 years. Dropouts were excluded from the study [21]. In 2015 Bramskamp et al. [22] published the results of their prospective follow up study. The authors included 214 patients and had 9 dropouts. Their mean follow-up period was 10 years. They did not publish data for the LDL-C reduction within the adherent patients. Only the mean LDL-C for the 148 adherent patients (149mg/dl) and for non-adherent patients (302mg/dl) was published [22]. Bogsrud et al. [23] conducted a retrospective study in 2018, reviewing records of 302 children visiting the Lipid Clinic of the Oslo university hospital. On average the children had been diagnosed 4,4 years before. Drop-out data is not included. The main decrease in LDL-C levels the authors recorded was 38% [23]. Considering the present study and all the other follow-up studies mentioned above there is still a lot of research to do in the field of long-term management of people affected by FH. Especially when thinking about the prevalence of FH and the easy treatment options when the condition is diagnosed and treated at a young age. The awareness for this metabolic disorder must be further increased in order to ensure the best possible care for FH patients.

The data of the present study on long-term treatment (mean 20 years) of patients who had been diagnosed with heterozygous FH at a young age show a mean reduction of LDL-C of 59,6%. No clinical signs of manifestation of cardiovascular diseases could have been observed during the follow-up period. No side effects of the lipidlowering therapy have been reported. Thus, it is concluded that long-term treatment of patients with FH beginning in childhood and adolescents is feasible and obviously successful.

1. Singh S, Bittner V (2015) Familial Hypercholesterolemia--epidemiology, diagnosis, and screening. Curr Atheroscler Rep 17(2): 482.
2. Libby P, Buring JE, Badimon L, Hansson GK, Deanfield J, et al. (2019) Atherosclerosis. Nat Rev Dis Primers 5(1): 56.
3. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, et al. (2013) Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: Guidance for clinicians to prevent coronary heart disease: Consensus statement of the european atherosclerosis society. European Heart Journal 34(45): 3478-3490.
4. Akioyamen LE, Genest J, Shan SD, Reel RL, Albaum JM, et al. (2017) Estimating the prevalence of heterozygous familial hypercholesterolaemia: A systematic review and meta- analysis. BMJ Open 7(9): e016461.
5. Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG (2020) Worldwide prevalence of familial hypercholesterolemia. Journal of the American College of Cardiology 75(20): 2553-2566.
6. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, et al. (2014) 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. European Heart Journal 35(32): 2146-2157.
7. Sjouke B, Kusters DM, Kindt I, Besseling J, Defesche JC, et al. (2015) Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: Prevalence, genotype-phenotype relationship, and clinical outcome. European Heart Journal 36(9): 560-565.
8. Robinson JG (2013) Management of familial hypercholesterolemia: A review of the recommendations from the national lipid association expert panel on familial hypercholesterolemia. JMCP 19(2): 139-149.
9. Representatives of the global familial hypercholesterolemia community, Wilemon KA, Patel J, Aguilar-Salinas C, Ahmed CD, et al. (2020) Reducing the clinical and public health burden of familial hypercholesterolemia: A global call to action. JAMA Cardiol 5(2): 217-229.
10. Berberich AJ, Hegele RA (2019) The complex molecular genetics of familial hypercholesterolaemia. Nat Rev Cardiol 16(1): 9-20.
11. Santos RD, Gidding SS, Hegele RA, Cuchel MA, Barter PJ, et al. (2016) Defining severe familial hypercholesterolaemia and the implications for clinical management: A consensus statement from the international atherosclerosis society severe familial hypercholesterolemia panel. The Lancet Diabetes & Endocrinology 4(10): 850-861.
12. Wiegman A, Gidding SS, Watts GF, Chapman MJ, Ginsberg HN, et al. (2015) Familial hypercholesterolaemia in children and adolescents: Gaining decades of life by optimizing detection and treatment. Eur Heart J 36(36): 2425-2437.
13. Widhalm K, Binder CB, Kreissl A, Aldover-Macasaet E, Fritsch M, et al. (2011) Sudden death in a 4-year-old boy: A near-complete occlusion of the coronary artery caused by an aggressive low-density lipoprotein receptor mutation (w556r) in homozygous familial hypercholesterolemia. The Journal of Pediatrics 158(1): 167.
14. Widhalm K, Benke IM, Fritz M, Geiger H, Helk O, et al. (2017) Homozygous familial hypercholesterolemia: Summarized case reports. Atherosclerosis 257: 86-89.
15. Katzmann JL, Lehmann M, Tünnemann-Tarr A, Haack IA, Dressel A, et al. (2021) Cutaneous manifestations in familial hypercholesterolaemia. Atherosclerosis 333: 116-123.
16. Raal FJ, Hovingh GK, Catapano AL (2018) Familial hypercholesterolemia treatments: Guidelines and new therapies. Atherosclerosis. 277: 483-492.
17. Humphries SE, Cooper J, Dale P, Ramaswami U (2018) The UK paediatric familial hypercholesterolaemia register: Statin-related safety and 1-year growth data. Journal of Clinical Lipidology 12(1): 25-32.
18. Kavey REW, Manlhiot C, Runeckles K, Collins T, Gidding SS, et al. (2020) Effectiveness and safety of statin therapy in children: A real-world clinical practice experience. CJC Open 2(6): 473-482.
19. Luirink IK, Wiegman A, Kusters DM, Hof MH, Groothoff JW, et al. (2019) 20-Year Follow-up of statins in children with familial hypercholesterolemia. N Engl J Med 381(16): 1547-1556.
20. Carreau V, Girardet JP, Bruckert E (2011) Long-term follow-up of statin treatment in a cohort of children with familial hypercholesterolemia: Efficacy and tolerability. Pediatric Drugs 13(4): 267-275.
21. Elis A, Zhou R, Stein EA (2014) Treatment of familial hypercholesterolaemia in children and adolescents in the last three decades. Cardiol Young 24(3): 437-441.
22. Braamskamp MJAM, Kusters DM, Avis HJ, Smets EMA, Wijburg F, et al. (2015) Long-term statin treatment in children with familial hypercholesterolemia: More insight into tolerability and adherence. Pediatr Drugs 17(2):159-166.
23. Bogsrud MP, Langslet G, Wium C, Johansen D, Svilaas A, et al. (2018) Treatment goal attainment in children with familial hypercholesterolemia: A cohort study of 302 children in Norway. Journal of Clinical Lipidology 12(2): 375-382.