Barriers to Early Diagnosis and Treatment of Familial Hypercholesterolemia: Current Perspectives on Improving Patient Care

Figures & data

Box 1 Some Known Barriers to Early Diagnosis and Management of Familial Hypercholesterolemia

Diagnosis

Physicians Knowledge of the disorder Awareness of current guidelines Identification of probable cases in different health care levels No uniform clinical criteria for diagnosis Screening methods (opportunistic, universal, cascade) Age to screen Lipid or metabolic disorder specialists (multidisciplinary and integrated with general practitioners) Availability of genetic testing

Patients Education to the family Awareness in the family Perception of risk

Cardiovascular risk:

Underestimation of risk

Other cardiovascular risk factors not identified and/or not controlled

Use of imaging like Coronary CT-scan or carotid ultrasound, and biomarkers (ie, lipoprotein(a)) to stratify risk.

Treatment:

LDL-C targets

Adherence to long-term lifestyle changes

Cost of medications

Access to new medications (iPCSK9)

Cost/effectiveness studies required

Adherence to long-term treatment

Mass-media and social network information

Registries

Development

Clinical information

Research

Audit

National programs for detection and management of FH

Health system

Policy-makers

Table 1 Criteria for Familial Hypercholesterolemia in Adults, Screening, Lipid-Lowering Treatment and LDL-C Targets According to Different Guidelines or Consensus Panels

	Spanish FH Foundation^Citation12	European Atherosclerosis Society Consensus Statement^Citation1 and ESC/EAS Guidelines 2019^Citation61	NICE-UK^Citation19	National Lipid Association 2011^Citation24 and AHA/ACC 2018^Citation74	Japan^Citation84
Criteria to suspect FH and to make diagnosis	18 years LDL-C > 220 and 1 of the following: -LDL-C >150 mg/dL in children -LDL-C > 190 mg/dL in adults -PCVD in IC or relative -Xanthoma in IC or relative unknown family history: LDL-C > 300 mg/dL	> 18 years TC > 310 mg/dL PCHD in case or family member Xanthoma in case or family member Sudden cardiac death in family member Then use DLCN criteria to make the diagnosis	> 16 years TC > 290 mg/dL LDL-C > 190 mg/dL Personal or family history of PCHD (before age 60 years) Then use Simon Broome or DLCN criteria to make diagnosis	> 20 years LDL-C > 190 mg/dL Non-HDL-C > 220 mg/dL Any validated sets of criteria can be used: US MEDPED, DLCN score, Simon Broome)	>15 years At least 2 of the following: LDL-C ≥ 180 mg/dL Tendon or tuberosum xanthomas History of FH or PCHD within 2nd degree relatives
DNA testing	IC with DLCN score ≥ 6 and then in cascade screening	Strongly recommended if DLCN score ≥6, and in cases with xanthomas and/or hypercholesterolemia plus PCHD Then in cascade screening	To confirm IC and then in cascade screening	Not needed for diagnosis	Is desirable to use genetic testing in cases suspected FH (those cases with only 1 criteria)
Lipid-lowering treatment	High intensity statin + ezetimibe In severe cases, consider to add PCSK9i	High intensity statin combined with Ezetimibe and/or Resins ESC/EAS 2019 PCSK9i are recommended in very-high-risk FH patients if the treatment goal is not achieved on maximal tolerated statin plus ezetimibe.	High intensity statin Ezetimibe combined with statin when LDL-C is not controlled with high intensity statin Ezetimibe in monotherapy when statins are contraindicated or not tolerated.	High intensity statin Consider to add Ezetimibe and resins AHA/ACC 2018 Patients 30–75 years with FH and with on- treatment LDL-C ≥100 mg/dL despite maximally tolerated statin and ezetimibe therapy, consider PCSK9i	Statins and up-titrate according efficacy and tolerability Consider ezetimibe and PCSK9i and others if more efficacy is required
Targets	LDL-C < 100 mg/dL in FH with at least 1 CVRF LDL-C < 70 mg/dL if CVD, T2DM and significant subclinical atherosclerosis are present Or at least 50% LDL-C reduction from baseline	LDL-C <100 mg/dL LDL-C < 70 in adults with FH and CHD or T2DM ESC/EAS 2019 LDL-C reduction ≥ 50% and LDL-C < 55 mg/dL should be considered in FH with ASCVD or with another major CVRF (very high risk), LDL-C reduction ≥ 50% and LDL-C < 70 mg/dL are recommended in FH without other major CVRF	Reduction of LDL-C ≥ 50%	Reduction of LDL-C ≥ 50% AHA/ACC Use LDL-C levels to add ezetimibe and then PCSK9i	In primary prevention, LDL-C < 100 mg/dL or LDL-C reduction ≥50% In secondary prevention, LDL-C <70 mg/dL

Note: Secondary causes should be excluded in all guidelines.

Abbreviations: EAS, European Atherosclerosis Society; NLA, National Lipid Association; DLCN, Dutch Lipid Clinical Network criteria; LDL-C, LDL-cholesterol; PCVD, premature cardiovascular disease; PCHD, premature coronary heart disease; CVRF, cardiovascular risk factor.

Figure 1 Attitude towards an adult with suspected familial Hypercholesterolemia according to different guidelines.

Table 2 Criteria for Familial Hypercholesterolemia in Children and Adolescents, Screening, Lipid-Lowering Treatment and LDL-C Targets According to Different Guidelines or Consensus Panels

	Spanish FH Foundation^Citation12	European Atherosclerosis Society^Citation27	Heart –UK Statement of care^Citation85	National Lipid Association 2011^Citation24 & AHA/ACC 2018^Citation74	Japan^Citation84
Criteria to suspect FH When to Screen	< 18 years: LDL-C > 190 mg/dL LDL-C > 150 mg/dL + high cholesterol and/or PCVD in one parent, or DNA+ in one parent Screen between age 2–8 years Cascade screening is recommended	< 18 years LDL-C > 190 mg/dL on 2 successive occasions after 3 month diet LDL-C > 160 mg/dL + PCHD and/or high cholesterol in one parent Screen from age 5 years	< 16 years LDL-C > 160 mg/dL by cascade screening or another reason) Screen by age 10	< 20 years LDL-C > 160 mg/dL Non HDL-C > 190 mg/dL Universal Screen at age 9–11 years Screen at age 2 if positive family history of hypercholesterolemia or PCHD or presence of other CVRF	< 15 years LDL-C 140 mg/dL (TC > 220 mg/dL) And family history of FH or PCHD Screen at age 10
DNA testing	FH-causing mutation known in parent	FH-Causing mutation known in parent; or if parent died from PCHD and child has hypercholesterolemia	FH-causing mutation known in parent	Not needed for diagnosis	Not considered in guidelines for heterozygous FH
Lipid-lowering treatment	Start statin at age 10 in boys and preferable after menarche in girls. Can be considered before in case of PCHD In Homozygous FH start at age 2 years.	Start statin at age 8–10 years old with lowest recommended dose and up-titrate according LDL-C and tolerability	Consider statin by age 10 years. Before 8 years if LDL-C > 190 mg/dL and positive family history of PCHD Consider ezetimibe	Consider statins at age 8 years. AHA/ACC 2018: LDL-C ≥160 mg/dL At age 10 years	Consider statin from age 10 if LDL-C is persistently ≥ 180 mg/dL despite lifestyle changes And <10 years if LDL-C ≥200 mg/dL
Targets	LDL-C < 130 mg/dL Consider < 160 mg/dL in children < age 14 if no other CVRF is present	>10 years: LDL-C < 130 mg/dL especially those with high risk conditions or CVRF 8–10 years: 50% reduction from baseline,	< 10 years: 30-50% reduction in LDL-C or LDL< 135 mg/dL ≥10 years: > 50% LDL_C reduction or LDL-C < 135 mg/dL ≥14 years: LDL-C < 100 mg/dL if other co-morbidities or strong family history of PCHD	LDL-C reduction ≥ 50% or LDL-C < 130 mg/dL More aggressive target should be considered if additional CVRF are present	LDL-C < 140 mg/dL

Note: Secondary causes should be excluded in all guidelines.

Abbreviations: EAS, European Atherosclerosis Society; NLA, National Lipid Association; LDL-C, LDL-cholesterol; PCVD, premature cardiovascular disease; PCHD, premature coronary heart disease; CVRF, cardiovascular risk factor.

Mata P, Alonso R, Ruiz A, et al. Diagnostico y tratamiento de la hipercolesterolemia familiar en Espana: documento de consenso. Aten Primaria. 2014. doi:10.1016/j.aprim.2013.12.015

 Google Scholar

Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease. Eur Heart J. 2013;34:3478–3490. doi:10.1093/eurheartj/eht273

 PubMed Web of Science ®Google Scholar

Mach F, Baigent C, Catapano A, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2019:ehz455. doi:10.1093/eurheartj/ehz455

 Web of Science ®Google Scholar

Wierzbicki AS, Humphries SE, Minhas R. Familial hypercholesterolaemia: summary of NICE guidance. BMJ. 2008;337:509–511. doi:10.1136/bmj.a1095

 Google Scholar

Goldberg A, Hopkins P, Toth P, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients. Clinical guidance from the national lipid association expert panel on familial hypercholesterolemia. Executive summary. J Clin Lipidol. 2011;5:S1–S8. doi:10.1016/j.jacl.2011.04.003

 PubMed Web of Science ®Google Scholar

Grundy SM, Stone NJ, Bailey AL, et al. AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guide- lines. Circulation. 2019;139:e1082- e1143. doi:10.1161/CIR.0000000000000625

 PubMed Web of Science ®Google Scholar

Harada-Shiba M, Arai H, Ishigaki Y, et al. Guidelines for diagnosis and treatment of familial hypercholesterolemia 2017. J Atheroscler Thromb. 2018;25:751–770. doi:10.5551/jat.CR003

 PubMed Web of Science ®Google Scholar

Wiegman A, Gidding SS, Watts GF, et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015;36:2425–2437. doi:10.1093/eurheartj/ehv157

 PubMed Web of Science ®Google Scholar

Ramaswami U, Humphries S, Priestley-Barnham L, et al. Current management of children and young people with heterozygous familial hypercholesterolemia- HEART UK statement of care. Atherosclerosis. 2019;290:1–8. doi:10.1016/j.atherosclerosis.2019.09.005

 PubMed Web of Science ®Google Scholar