A Personalized Medicine Approach is Best for Patients with Homozygous Familial Hypercholesterolemia
Main Article Content
Abstract
Homozygous familial hypercholesterolemia (HoFH) is an autosomal semi-dominant condition characterized by biallelic pathogenic variants impacting low-density lipoprotein receptor (LDLR) function. Affected individuals have severely elevated LDL cholesterol, early onset atherosclerotic heart disease and/or aortic stenosis, and characteristic clinical findings. While the cause is known and diagnosis is relatively simple, real-world HoFH care presents many complexities, including genetic heterogeneity and the diverse personal and social circumstances that influence care. Genetics-informed treatment involves a trial- and-error approach that warrants specific considerations during pregnancy. Thus, HoFH care requires a deep understanding of personal factors, social determinants of health, and a flexible, adaptable approach to treatment, all of which justify the need for personalized care. Framed by complexity theory, this review offers strategies for personalizing HoFH care, including a reconceptualization of the definition of health and implementing a multidisciplinary team approach. We also recommend integrating complexity theory and systems thinking into clinical care. By doing so, we illustrate the advantages of classifying knowledge complexity to inform clinical decision-making. We also demonstrate how openness to relationship-building and time investment is critical to materializing personalized care to HoFH.
Article Details
How to Cite
MORALES, Ana et al.
A Personalized Medicine Approach is Best for Patients with Homozygous Familial Hypercholesterolemia.
Medical Research Archives, [S.l.], v. 12, n. 12, dec. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6160>. Date accessed: 06 jan. 2025.
doi: https://doi.org/10.18103/mra.v12i12.6160.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
Cuchel M, Raal FJ, Hegele RA, et al. 2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance. Eur Heart J. 2023;44(25):2277-2291.
2. Watts GF, Gidding SS, Mata P, et al. Familial hypercholesterolaemia: evolving knowledge for designing adaptive models of care. Nat Rev Cardiol. 2020;17(6):360-377.
3. Gidding SS, Hegele RA. Introducing Personalized Medicine Into Pediatric Homozygous Familial Hypercholesterolemia Care. Arterioscler Thromb Vasc Biol. 2022;42(12):1458-1460.
4. Sturmberg, J.P., & Martin, C. Complexity in Health: An Introduction. In: Sturmberg, J.P., & Martin, C., ed. Handbook of Systems and Complexity in Health. ; 2013.
5. Braithwaite J. Changing how we think about healthcare improvement. BMJ. 2018;361:k2014.
6. Ellis B. An Overview of Complexity Theory: Understanding Primary Care as a Complex Adaptive System. In: Sturmberg, J.P., & Martin, C., ed. Handbook of Systems and Complexity in Health. ; 2013.
7. Di Taranto MD, Giacobbe C, Fortunato G. Familial hypercholesterolemia: A complex genetic disease with variable phenotypes. Eur J Med Genet. 2020;63(4):103831.
8. Sturmberg JP. Health: A Personal Complex-Adaptive State. In: Sturmberg JP, Martin CM, eds. Handbook of Systems and Complexity in Health. Springer New York; 2013:231-242.
9. Sturmberg, J.P., O’Halloran, D.M & Martin, C.M. Chapter 47: Healthcare Reform: The Need for a Complex Adaptive Systems Approach. In: Sturmberg, J.P., & Martin, C., ed. Handbook of Systems and Complexity in Health. ; 2013.
10. Gray B. The Cynefin framework: applying an understanding of complexity to medicine. J Prim Health Care. 2017;9(4):258-261.
11. Sturmberg JP, Miles A. The Complex Nature of Knowledge. Handbook of Systems and Complexity in Health. Published online 2013:39-62. doi:10.1007/978-1-4614-4998-0_4
12. Kurtz CF, Snowden DJ. The new dynamics of strategy: Sense-making in a complex and complicated world. IBM Syst J. 2003;42(3):462-483.
13. Tromp TR, Hartgers ML, Hovingh GK, et al. Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study. Lancet. 2022;399(10326):719-728.
14. Berberich AJ, Hegele RA. A modern approach to dyslipidemia. Endocr Rev. 2022;43(4):611-653.
15. Lee J, Hegele RA. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J Inherit Metab Dis. 2014;37(3):333-339.
16. Burnett JR, Hooper AJ, Hegele RA. APOB-related familial hypobetalipoproteinemia. In: GeneReviews(®). University of Washington, Seattle; 1993.
17. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37(2):161-165.
18. DeBarber AE, Duell PB. Update on cerebrotendinous xanthomatosis. Curr Opin Lipidol. 2021;32(2):123-131.
19. Berberich AJ, Hegele RA. The advantages and pitfalls of genetic analysis in the diagnosis and management of lipid disorders. Best Pract Res Clin Endocrinol Metab. 2023;37(3):101719.
20. Raal FJ, Hegele RA, Ruzza A, et al. Evolocumab treatment in pediatric patients with homozygous familial hypercholesterolemia: Pooled data from three open-label studies. Arterioscler Thromb Vasc Biol. 2024;44(5):1156-1164.
21. Wiegman A, Greber-Platzer S, Ali S, et al. Evinacumab for pediatric patients with homozygous familial hypercholesterolemia. Circulation. 2024;149(5):343-353.
22. Masana L, Zambon A, Schmitt CP, et al. Lomitapide for the treatment of paediatric patients with homozygous familial hypercholesterolaemia: results from the efficacy phase of APH-19, a phase 3, open-label study. Lancet Diabetes Endocrinol.
23. Gianos E, Duell PB, Toth PP, et al. Lipoprotein apheresis: Utility, outcomes, and implementation in clinical practice: A scientific statement from the American heart association. Arterioscler Thromb Vasc Biol. Published online October 7, 2024. doi:10.1161/ATV.0000000000000177
24. Reijman MD, Kusters DM, Groothoff JW, et al. Clinical practice recommendations on lipoprotein apheresis for children with homozygous familial hypercholesterolaemia: An expert consensus statement from ERKNet and ESPN. Atherosclerosis. 2024;392(117525):117525.
25. Sinzinger H, Steiner S, Derfler K. Pleiotropic effects of regular lipoprotein-apheresis. Atheroscler Suppl. 2017;30:122-127.
26. van Wijk DF, Sjouke B, Figueroa A, et al. Nonpharmacological lipoprotein apheresis reduces arterial inflammation in familial hypercholesterolemia. J Am Coll Cardiol. 2014;64(14):1418-1426.
27. Schettler VJJ, Selke N, Jenke S, et al. The German Lipoprotein Apheresis Registry-Summary of the eleventh annual report. Atherosclerosis. 2024;398(118601):118601.
28. Reijman MD, Tromp TR, Hutten BA, et al. Cardiovascular outcomes in patients with homozygous familial hypercholesterolaemia on lipoprotein apheresis initiated during childhood: long-term follow-up of an international cohort from two registries. Lancet Child Adolesc Health. 2024;8(7):491-499.
29. Alothman L, Bélanger AM, Ruel I, et al. Health-related quality of life in homozygous familial hypercholesterolemia: A systematic review and meta-analysis. J Clin Lipidol. 2022;16(1):52-65.
30. Kayikcioglu M, Kuman-Tunçel O, Pirildar S, et al. Clinical management, psychosocial characteristics, and quality of life in patients with homozygous familial hypercholesterolemia undergoing LDL-apheresis in Turkey: Results of a nationwide survey (A-HIT1 registry). J Clin Lipidol. 2019;13(3):455-467.
31. Gidding SS, Ballantyne CM, Cuchel M, et al. It is time to screen for homozygous familial hypercholesterolemia in the United States. Glob Heart. 2024;19(1):43.
32. Social Determinants of Health. August 2, 2021. Accessed October 17, 2024. https://health.gov/healthypeople/priority-areas/social-determinants-health
33. Mulder JWCM, Kranenburg LW, Treling WJ, et al. Quality of life and coping in Dutch homozygous familial hypercholesterolemia patients: A qualitative study. Atherosclerosis. 2022;348:75-81.
34. Celentano D, Moyses S. Epidemiology and Public Policy. In: Celentano D, Moyses S, eds. Gordis Epidemiology. Elsevier, Inc.; 2019.
35. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics—2022 Update: A Report From the American Heart Association. Circulation. 2022;145(8). doi:10.1161/cir.0000000000001052
36. Powell-Wiley TM, Baumer Y, Baah FO, et al. Social determinants of cardiovascular disease. Circ Res. 2022;130(5):782-799.
37. Brandt EJ, Tobb K, Cambron JC, et al. Assessing and addressing social determinants of cardiovascular health: JACC state-of-the-art review. J Am Coll Cardiol. 2023;81(14):1368-1385.
38. Ison HE, Clarke SL, Knowles JW. Familial Hypercholesterolemia. In: Adam MP, Feldman J, Mirzaa GM, et al., eds. GeneReviews®. University of Washington, Seattle; 2014.
39. Tromp TR, Reijman MD, Wiegman A, et al. Counseling couples at risk of having a child with homozygous familial hypercholesterolemia - Clinical experience and recommendations. J Clin Lipidol. 2023;17(2):291-296.
40. Reijman MD, Defesche JC, Wiegman A. Genotype-phenotype correlation in a large cohort of pediatric patients with heterozygous and homozygous familial hypercholesterolemia. Curr Opin Lipidol. 2023;34(6):287-295.
41. Rothstein MA. Currents in contemporary ethics. GINA, the ADA, and genetic discrimination in employment. J Law Med Ethics. 2008;36(4):837-840.
42. Hudson KL. Genomics, health care, and society. Obstet Gynecol Surv. 2012;67(1):24-26.
43. American Medical Association. Genetic discrimination. American Medical Association. April 28, 2022. Accessed October 4, 2024. https://www.ama-assn.org/delivering-care/precision-medicine/genetic-discrimination
44. Joly Y, Ngueng Feze I, Simard J. Genetic discrimination and life insurance: a systematic review of the evidence. BMC Med. 2013;11(1):25.
45. Wauters A, Van Hoyweghen I. Global trends on fears and concerns of genetic discrimination: a systematic literature review. J Hum Genet. 2016;61(4):275-282.
46. Snowden DJ, Boone ME. A leader’s framework for decision making. A leader's framework for decision making. Harv Bus Rev. 2007;85(11):68-76, 149.
47. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.
48. VanDyke RE, Hashimoto S, Morales A, Pyatt RE, Sturm AC. Impact of variant reclassification in the clinical setting of cardiovascular genetics. J Genet Couns. 2021;30(2):503-512.
49. Kayikcioglu M, Tokgozoglu L, Tuncel OK, Pirildar S, Can L. Negative impact of COVID-19 pandemic on the lifestyle and management of patients with homozygous familial hypercholesterolemia. J Clin Lipidol. 2020;14(6):751-755.
50. Ranmuthugala G, Plumb JJ, Cunningham FC, Georgiou A, Westbrook JI, Braithwaite J. How and why are communities of practice established in the healthcare sector? A systematic review of the literature. BMC Health Serv Res. 2011;11(1):1-16.
51. Cantillon P, D’Eath M, De Grave W, Dornan T. How do clinicians become teachers? A communities of practice perspective. Adv Health Sci Educ Theory Pract. 2016;21(5):991-1008.
52. Wenger E. Communities of Practice and Social Learning Systems: the Career of a Concept. In: Blackmore C, ed. Social Learning Systems and Communities of Practice. Springer; 2010:179-198.
53. Introduction to communities of practice - wenger-trayner. wenger-trayner - Social learning theorists and consultants. January 12, 2022. Accessed April 10, 2023. https://www.wenger-trayner.com/introduction-to-communities-of-practice/
54. Paley J. Complex adaptive systems and nursing. Nurs Inq. 2007;14(3):233-242.
55. Flieger SP. Implementing the patient-centered medical home in complex adaptive systems: Becoming a relationship-centered patient-centered medical home. Health Care Manage Rev. 2017;42(2):112-121.
2. Watts GF, Gidding SS, Mata P, et al. Familial hypercholesterolaemia: evolving knowledge for designing adaptive models of care. Nat Rev Cardiol. 2020;17(6):360-377.
3. Gidding SS, Hegele RA. Introducing Personalized Medicine Into Pediatric Homozygous Familial Hypercholesterolemia Care. Arterioscler Thromb Vasc Biol. 2022;42(12):1458-1460.
4. Sturmberg, J.P., & Martin, C. Complexity in Health: An Introduction. In: Sturmberg, J.P., & Martin, C., ed. Handbook of Systems and Complexity in Health. ; 2013.
5. Braithwaite J. Changing how we think about healthcare improvement. BMJ. 2018;361:k2014.
6. Ellis B. An Overview of Complexity Theory: Understanding Primary Care as a Complex Adaptive System. In: Sturmberg, J.P., & Martin, C., ed. Handbook of Systems and Complexity in Health. ; 2013.
7. Di Taranto MD, Giacobbe C, Fortunato G. Familial hypercholesterolemia: A complex genetic disease with variable phenotypes. Eur J Med Genet. 2020;63(4):103831.
8. Sturmberg JP. Health: A Personal Complex-Adaptive State. In: Sturmberg JP, Martin CM, eds. Handbook of Systems and Complexity in Health. Springer New York; 2013:231-242.
9. Sturmberg, J.P., O’Halloran, D.M & Martin, C.M. Chapter 47: Healthcare Reform: The Need for a Complex Adaptive Systems Approach. In: Sturmberg, J.P., & Martin, C., ed. Handbook of Systems and Complexity in Health. ; 2013.
10. Gray B. The Cynefin framework: applying an understanding of complexity to medicine. J Prim Health Care. 2017;9(4):258-261.
11. Sturmberg JP, Miles A. The Complex Nature of Knowledge. Handbook of Systems and Complexity in Health. Published online 2013:39-62. doi:10.1007/978-1-4614-4998-0_4
12. Kurtz CF, Snowden DJ. The new dynamics of strategy: Sense-making in a complex and complicated world. IBM Syst J. 2003;42(3):462-483.
13. Tromp TR, Hartgers ML, Hovingh GK, et al. Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study. Lancet. 2022;399(10326):719-728.
14. Berberich AJ, Hegele RA. A modern approach to dyslipidemia. Endocr Rev. 2022;43(4):611-653.
15. Lee J, Hegele RA. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J Inherit Metab Dis. 2014;37(3):333-339.
16. Burnett JR, Hooper AJ, Hegele RA. APOB-related familial hypobetalipoproteinemia. In: GeneReviews(®). University of Washington, Seattle; 1993.
17. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37(2):161-165.
18. DeBarber AE, Duell PB. Update on cerebrotendinous xanthomatosis. Curr Opin Lipidol. 2021;32(2):123-131.
19. Berberich AJ, Hegele RA. The advantages and pitfalls of genetic analysis in the diagnosis and management of lipid disorders. Best Pract Res Clin Endocrinol Metab. 2023;37(3):101719.
20. Raal FJ, Hegele RA, Ruzza A, et al. Evolocumab treatment in pediatric patients with homozygous familial hypercholesterolemia: Pooled data from three open-label studies. Arterioscler Thromb Vasc Biol. 2024;44(5):1156-1164.
21. Wiegman A, Greber-Platzer S, Ali S, et al. Evinacumab for pediatric patients with homozygous familial hypercholesterolemia. Circulation. 2024;149(5):343-353.
22. Masana L, Zambon A, Schmitt CP, et al. Lomitapide for the treatment of paediatric patients with homozygous familial hypercholesterolaemia: results from the efficacy phase of APH-19, a phase 3, open-label study. Lancet Diabetes Endocrinol.
23. Gianos E, Duell PB, Toth PP, et al. Lipoprotein apheresis: Utility, outcomes, and implementation in clinical practice: A scientific statement from the American heart association. Arterioscler Thromb Vasc Biol. Published online October 7, 2024. doi:10.1161/ATV.0000000000000177
24. Reijman MD, Kusters DM, Groothoff JW, et al. Clinical practice recommendations on lipoprotein apheresis for children with homozygous familial hypercholesterolaemia: An expert consensus statement from ERKNet and ESPN. Atherosclerosis. 2024;392(117525):117525.
25. Sinzinger H, Steiner S, Derfler K. Pleiotropic effects of regular lipoprotein-apheresis. Atheroscler Suppl. 2017;30:122-127.
26. van Wijk DF, Sjouke B, Figueroa A, et al. Nonpharmacological lipoprotein apheresis reduces arterial inflammation in familial hypercholesterolemia. J Am Coll Cardiol. 2014;64(14):1418-1426.
27. Schettler VJJ, Selke N, Jenke S, et al. The German Lipoprotein Apheresis Registry-Summary of the eleventh annual report. Atherosclerosis. 2024;398(118601):118601.
28. Reijman MD, Tromp TR, Hutten BA, et al. Cardiovascular outcomes in patients with homozygous familial hypercholesterolaemia on lipoprotein apheresis initiated during childhood: long-term follow-up of an international cohort from two registries. Lancet Child Adolesc Health. 2024;8(7):491-499.
29. Alothman L, Bélanger AM, Ruel I, et al. Health-related quality of life in homozygous familial hypercholesterolemia: A systematic review and meta-analysis. J Clin Lipidol. 2022;16(1):52-65.
30. Kayikcioglu M, Kuman-Tunçel O, Pirildar S, et al. Clinical management, psychosocial characteristics, and quality of life in patients with homozygous familial hypercholesterolemia undergoing LDL-apheresis in Turkey: Results of a nationwide survey (A-HIT1 registry). J Clin Lipidol. 2019;13(3):455-467.
31. Gidding SS, Ballantyne CM, Cuchel M, et al. It is time to screen for homozygous familial hypercholesterolemia in the United States. Glob Heart. 2024;19(1):43.
32. Social Determinants of Health. August 2, 2021. Accessed October 17, 2024. https://health.gov/healthypeople/priority-areas/social-determinants-health
33. Mulder JWCM, Kranenburg LW, Treling WJ, et al. Quality of life and coping in Dutch homozygous familial hypercholesterolemia patients: A qualitative study. Atherosclerosis. 2022;348:75-81.
34. Celentano D, Moyses S. Epidemiology and Public Policy. In: Celentano D, Moyses S, eds. Gordis Epidemiology. Elsevier, Inc.; 2019.
35. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics—2022 Update: A Report From the American Heart Association. Circulation. 2022;145(8). doi:10.1161/cir.0000000000001052
36. Powell-Wiley TM, Baumer Y, Baah FO, et al. Social determinants of cardiovascular disease. Circ Res. 2022;130(5):782-799.
37. Brandt EJ, Tobb K, Cambron JC, et al. Assessing and addressing social determinants of cardiovascular health: JACC state-of-the-art review. J Am Coll Cardiol. 2023;81(14):1368-1385.
38. Ison HE, Clarke SL, Knowles JW. Familial Hypercholesterolemia. In: Adam MP, Feldman J, Mirzaa GM, et al., eds. GeneReviews®. University of Washington, Seattle; 2014.
39. Tromp TR, Reijman MD, Wiegman A, et al. Counseling couples at risk of having a child with homozygous familial hypercholesterolemia - Clinical experience and recommendations. J Clin Lipidol. 2023;17(2):291-296.
40. Reijman MD, Defesche JC, Wiegman A. Genotype-phenotype correlation in a large cohort of pediatric patients with heterozygous and homozygous familial hypercholesterolemia. Curr Opin Lipidol. 2023;34(6):287-295.
41. Rothstein MA. Currents in contemporary ethics. GINA, the ADA, and genetic discrimination in employment. J Law Med Ethics. 2008;36(4):837-840.
42. Hudson KL. Genomics, health care, and society. Obstet Gynecol Surv. 2012;67(1):24-26.
43. American Medical Association. Genetic discrimination. American Medical Association. April 28, 2022. Accessed October 4, 2024. https://www.ama-assn.org/delivering-care/precision-medicine/genetic-discrimination
44. Joly Y, Ngueng Feze I, Simard J. Genetic discrimination and life insurance: a systematic review of the evidence. BMC Med. 2013;11(1):25.
45. Wauters A, Van Hoyweghen I. Global trends on fears and concerns of genetic discrimination: a systematic literature review. J Hum Genet. 2016;61(4):275-282.
46. Snowden DJ, Boone ME. A leader’s framework for decision making. A leader's framework for decision making. Harv Bus Rev. 2007;85(11):68-76, 149.
47. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.
48. VanDyke RE, Hashimoto S, Morales A, Pyatt RE, Sturm AC. Impact of variant reclassification in the clinical setting of cardiovascular genetics. J Genet Couns. 2021;30(2):503-512.
49. Kayikcioglu M, Tokgozoglu L, Tuncel OK, Pirildar S, Can L. Negative impact of COVID-19 pandemic on the lifestyle and management of patients with homozygous familial hypercholesterolemia. J Clin Lipidol. 2020;14(6):751-755.
50. Ranmuthugala G, Plumb JJ, Cunningham FC, Georgiou A, Westbrook JI, Braithwaite J. How and why are communities of practice established in the healthcare sector? A systematic review of the literature. BMC Health Serv Res. 2011;11(1):1-16.
51. Cantillon P, D’Eath M, De Grave W, Dornan T. How do clinicians become teachers? A communities of practice perspective. Adv Health Sci Educ Theory Pract. 2016;21(5):991-1008.
52. Wenger E. Communities of Practice and Social Learning Systems: the Career of a Concept. In: Blackmore C, ed. Social Learning Systems and Communities of Practice. Springer; 2010:179-198.
53. Introduction to communities of practice - wenger-trayner. wenger-trayner - Social learning theorists and consultants. January 12, 2022. Accessed April 10, 2023. https://www.wenger-trayner.com/introduction-to-communities-of-practice/
54. Paley J. Complex adaptive systems and nursing. Nurs Inq. 2007;14(3):233-242.
55. Flieger SP. Implementing the patient-centered medical home in complex adaptive systems: Becoming a relationship-centered patient-centered medical home. Health Care Manage Rev. 2017;42(2):112-121.