Screening, Diagnosis, and Treatment of Familial Hypercholesterolemia: Symposium of the Education Committee, Korean Society of Lipid and Atherosclerosis

Chan Joo Lee; Ji Hyun Lee; Seonghoon Choi; Shin-Hye Kim; Hyun-Jae Kang; Sang-Hak Lee; Kyong Soo Park

doi:10.12997/jla.2018.7.2.122

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Lee, Lee, Choi, Kim, Kang, Lee, and Park: Screening, Diagnosis, and Treatment of Familial Hypercholesterolemia: Symposium of the Education Committee, Korean Society of Lipid and Atherosclerosis

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Journal of Lipid and Atherosclerosis 2018; 7(2): 122-154.

Published online: 27 August 2018

DOI: https://doi.org/10.12997/jla.2018.7.2.122

Screening, Diagnosis, and Treatment of Familial Hypercholesterolemia: Symposium of the Education Committee, Korean Society of Lipid and Atherosclerosis

Chan Joo Lee¹, Ji Hyun Lee², Seonghoon Choi³, Shin-Hye Kim⁴, Hyun-Jae Kang⁵, Sang-Hak Lee⁶, Kyong Soo Park^7,⁸

¹Department of Health Promotion, Yonsei University College of Medicine, Seoul, Korea.

²Department of Clinical Pharmacology and Therapeutics, Kyung Hee University College of Medicine, Seoul, Korea.

³Division of Cardiology, Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea.

⁴Department of Pediatrics, Inje University Sanggye Paik Hospital, Seoul, Korea.

⁵Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, Seoul, Korea.

⁶Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

⁷Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

⁸Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.

Correspondence to Sang-Hak Lee. Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. shl1106@yuhs.ac

The Korean Society of Lipid and Atherosclerosis

(open-access):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Familial hypercholesterolemia (FH) is typically associated with single gene mutation that is inherited by autosomal dominant manner. Due to high cardiovascular risk, aggressive discovery, diagnosis, and treatment of FH are critical. Although FH is being increasingly spotlighted, we do not have sufficient data on Korean patients with FH. Here, we present the content of symposium of the Education Committee, Korean Society of Lipid and Atherosclerosis held in May 2018: 1) epidemiology, clinical diagnosis, Korean FH data, and regulation in Korea; 2) genes associated with FH, sequencing process in suspicious proband, cascade screening, and difficulty in genetic diagnosis in FH; 3) the importance of lipid-lowering therapy in FH, conventional and novel therapeutics for FH; 4) diagnosis of FH in children and adolescence, screening, and treatment of FH in children and adolescence; 5) history of FH studies in Korea, the structure and current status of FH registry of Korean Society of Lipid and Atherosclerosis; and 6) difficulty in diagnosis of heterozygous and homozygous FH, drug intolerance and achievement of treatment target. Discussion between speakers and panels were also added. We hope that this article is helpful for understanding FH and future studies performed in Korea.

Keywords: Lipids, Atherosclerosis, Genetics, Mutation

Figures and Tables

Fig. 1

Receiver operating characteristic curves for total cholesterol and LDL-C and the presence of putative pathogenic variant carreirs. The best threshold values identified with the sum of sensitivity and specificity are indicated (from reference Shin et al.4 with permission).

LDL-C, low-density lipoprotein-cholesterol; TC, total cholesterol; AUC, area under the curve.

Fig. 2

Serial single-gene testing and multi-gene panel testing.

Fig. 3

A flow example of screening and interpretation of variants potentially causing FH.

FH, familial hypercholesterolemia; NGS, next-generation sequencing; SNV, single nucleotide variant; CNV, copy number variation.

Fig. 4

LDL-C burden in individual with or without FH as a function of the age of initiation of statin therapy (from Nordestgaard et al.7 Permission waived).

LDL-C, low-density lipoprotein-cholesterol; FH, familial hypercholesterolemia; hoFH, homozygous familial hypercholesterolemia; heFH, heterozygous familial hypercholesterolemia; HDL-C, high-density lipoprotein-cholesterol; CHD, coronary heart disease; TG, triglyceride.

Table 1

Four clinical diagnostic criteria of FH

Variables	Simon Broome	Dutch		MEDPED		Japan
Process	Definite: 1+ (2 or 3)	Definite: >8 points		Diagnosed if cholesterol level exceeds cut-points		2 out of 3 items are needed
	Possible: 1+ (4 or 5)	Probable: 6–8 points		Numbers in parenthesis indicate LDL-C
		Possible: 3–5 points
		Unlikely: <3 points
Items	1) TC >290 or LDL-C >190	1) Family history		1st relative with FH		LDL-C ≥180
	2) Tendon xanthoma in proband or in 1st or 2nd relative		1st relative with premature^† CAD or vascular disease (1)		<20 years: 220 (155)		Tendon xanthoma or Achilles tendo hypertrophy or xanthoma tuberosum
	3) DNA evidence of mutation in LDLR, APOB or PCSK9		1st relative with LDL-C >95 percentile (1)		20–29 years: 240 (170)		Family history of FH or premature^‡ CAD (within 2nd relative)
	4) TC >290 or LDL-C >190 in 1st or 2nd relative		1st relative with tendon xanthoma or arcus cornealis (2)		30–39 years: 270 (190)	LDL-C 250 strongly suggests FH
	5) Premature^* MI in 1st or 2nd degree relative		Children with LDL-C >95 percentile (2)		≥40 years: 290 (205)
		2) Clinical history		General population
			Premature CAD (2)		<20 years: 270 (200)
			Premature cerebral or peripheral vascular disease (1)		20–29 years: 290 (220)
		3) Physical examination			30–39 years: 340 (240)
			Tendon xanthoma (6)		≥40 years: 360 (260)
			Arcus cornealis <45 years (4)
		4) LDL-C
			≥325 (8)
			251–325 (5)
			191–250 (3)
			155–190 (1)
		5) DNA analysis
			Functional mutation in LDLR, APOB or PCSK9 (8)

FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein-cholesterol; TC, total cholesterol; MI, myocardial infarction; CAD, coronary artery disease.

^*Men <50 years or women <60 years; ^†men <55 years or women <60 years; ^‡men <55 years or women <65 years.

Table 2

Classification of variants' pathogenicity by the ACMG recommendation

Pathogenicity	Example of properties of variants
Disease causing	Well known functional mutations seen in multiple families
Disease causing	Tend to lead to very abnormal protein
Likely disease causing	Not quite as much support in segregation analysis
Likely disease causing	Less data but of the type expected to cause disease
Uncertain significance	VUS
Uncertain significance	Minor changes in protein, maybe “novel”
Likely benign or benign	Seen in normal people

ACMG, American College of Medical Genetics; VUS, variants of unknown significance.

Table 3

Studies of PCSK9 inhibitors in patients with FH

Variables	TESLA part B	REGN727/SAR236553	RUTHERFORD
Agent	Evolocumab	Alirocumab	Evolocumab
Phase	3	2	2
Study subjects & number	hoFH, 50	heFH, 77	heFH, 168
Major findings	LDL-C reduction by 31%	Dose dependent LDL-C reduction by 29%–68%, compared to 11% reduction with placebo	Dose dependent LDL-C reduction by 43%–55%, compared to 3% increase with placebo
References	Raal et al.11	Stein et al.12	Raal et al.13

FH, familial hypercholesterolemia; hoFH, homozygous familial hypercholesterolemia; heFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein-cholesterol.

Table 4

Diagnostic criteria of FH in children and adolescence

Variables	Europe	Simon Broome	US	MEDPED
LDL-C	≥190 mg/dL after 3M of diet intervention	≥155 mg/dL plus physical findings or family history	≥160 mg/dL or non-HDL-C ≥190 mg/dL	≥200 mg/dL in general population
LDL-C	≥160 mg/dL plus family history ≥130 mg/dL & parent has genetic Dx of FH	≥155 mg/dL plus physical findings or family history	≥160 mg/dL or non-HDL-C ≥190 mg/dL	≥155 mg/dL with family history
Physical findings		Tendon xanthoma
Family history	Premature CHD and/or high cholesterol	Xanthoma and/or myocardial infarction or high cholesterol		FH
Genetic	Detection of FH-causing mutation is gold standard	FH-causing mutation
Others	LDL-C should be measured at least ≥2 times/3 months
Others	Secondary causes should be ruled out
References	Wiegman et al.14 and Stock.15		Daniels et al.16

FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein-cholesterol; Dx, diagnosis; CHD, coronary heart disease; HDL-C, high-density lipoprotein-cholesterol.

Table 5

Treatment of hypercholesterolemia in children and adolescence

10세 이상		10세 미만
6개월간의 생활습관 교정, 식사요법 후에도 다음과 같은 경우에 고려함.		일반적으로 약물치료를 하지 않으나, 다음의 경우 제한적으로 고려함.
	1) LDL-C ≥190 mg/dL		1) hoFH, LDL-C ≥400 mg/dL, TG ≥500 mg/dL, 심혈관질환, 심장이식력이 있는 경우
	2) LDL-C ≥160–189 mg/dL 이면서 조기 심혈관질환 가족력 혹은 1가지 이상 고위험인자 혹은 2가지 이상 중등도 위험인자		2) 생활습관 교정, 식사요법 후에도 LDL-C ≥190 mg/dL 이면서 직계가족 중 조기 심혈관질환 가족력 혹은 1가지 이상 고위험인자 혹은 2가지 이상 중등도 위험인자
	3) LDL-C ≥130–159 mg/dL 이면서 2가지 이상 고위험인자 혹은 1가지 이상 고위험인자와 2가지 이상 중등도 위험인자 혹은 임상적인 심혈관질환
소아청소년 이상지질혈증 진료지침 2017		소아청소년 이상지질혈증 진료지침 2017

LDL-C, low-density lipoprotein-cholesterol; hoFH, homozygous familial hypercholesterolemia; TG, triglyceride.

Table 6

Inclusion criteria for Korean Society of Lipid and Atherosclerosis FH registry (2015)

No.	가족성 고콜레스테롤혈증 이형접합체 환자 (Simon Broome 기준)
1	1) Definite FH (아래 중 최소 한 가지를 만족할 때)
		A. 콜레스테롤 기준에 맞으면서 본인이나 일, 이차 친척에게 건의 황색종이 있는 경우
		B. LDLR 돌연변이, familial defective apoB100, PCSK9에 유전자 기반 증거가 있는 경우
	2) Possible FH (콜레스테롤 기준을 만족하고 아래 기준 중 최소 한 가지를 만족할 때)
		A. 관상동맥질환의 가족력: 이차 친척 중 50세 미만, 일차 친척 중 60세 미만
		B. 고콜레스테롤혈증의 가족력: 일, 이차 친척 중 TC 기준을 만족하는 사람이 있는 경우
2	1에 해당하는 환자 중 관상동맥질환의 가족력이 있거나, 진단 시 나이가 불분명하거나, 가족의 콜레스테롤 수치 자료가 없는 경우라도 본인의 LDL-C >190 mg/dL인 경우
3	가족력 확인이 불가능한 경우 본인의 LDL-C >225 mg/dL 인 경우
4	1, 2, 3에 해당하는 환자의 부모, 형제, 자녀, 조부모, 부모의 형제

FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein-cholesterol.

Table 7

Clinical characteristics of enrolled probands

Variables		Values (n=79)
Age (yr)		51.7 ± 14.5
Male (%)		34 (43)
CAD (%)		15 (20.0)
Family history of CAD or hypercholesterolemia (%)		47 (59.5)
Xanthoma		15 (20.0)
Body mass index (kg/m²)		24.2 ± 3.7
Laboratory values (mg/dL)
	TC	299 ± 44
	TG	147 ± 79
	HDL-C	52.6 ± 11.8
	LDL-C	223 ± 41
Definite:Possible		17:37

CAD, coronary artery disease; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; TC, total cholesterol; TG, triglyceride.

Table 8

Cases of FH diagnosed with three different diagnostic criteria

Cases	Proband	Family history	SB	D	M
M/46	Stabla angina; xanthoma(+); atorvastatin 20 mg; TC 244, LDL-C 176	Father-xanthoma; sister-xanthoma, hypercholesterolemia; son-TC >300; daughter-normal	+/−	+++	+/−
F/61	TC 286, LDL-C 207	Mother-MI; Younger brother-TC >300	+++	+	−
F/42	TC 274, LDL-C 212	Mother-sudden death at 55Y; maternal uncle-sudden death at 55Y; no siblings	+/−	+	−
F/28	TC 306, LDL-C 235	Grandfather-died by heart disease; father-CABG, hypercholesterolemia	+/−	+	+++
M/48	Xanthoma(+); TC 264, LDL-C 209	None	+++	+++	−
F/67	TC 335, LDL-C 221	Mother-died by CVA at 81Y	−	+	−
Number of diagnosed patients			2	6	1

FH, familial hypercholesterolemia; SB, Simon Broome; D, Dutch; M, MEDPED; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; CABG, coronary artery bypass graft; CVA, cerebrovascular accident.

Table 9

European Atherosclerosis Society diagnostic criteria for hoFH (2014)

Component
1. Two disease-causing allele affecting 4 genes (LDLR, APOB, PCSK9, or LDLRAP1) or
2. LDL-C >500 mg/dL in adult plus xanthoma at <10 years old (genetic diagnosis preferred) or >300 mg/dL after treatment plus xanthoma at <10 years old
3. Cholesterol levels mentioned above plus genetic heFH of both parents

hoFH, homozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein-choelserol; heFH, heterozygous familial hypercholesterolemia.

Table 10

A case of FH patients with difficulty for achieving treatment target

	M/53
Chief complaint	Hypercholesterolemia for 10 years; stable angina
Past history	CABG for 3-vessel diseases 10 years ago; known LDLR mutation (+)
Family history	Parents: unknown; elder sister: TC >400; son: hypercholesterolemia
Physical findings	Xanthoma (+)
Laboratory values & treatment	TC 421; TG 150; HDL-C 41; LDL-C 334	Atorvastatin 40 mg
	TC 270; TG 151; HDL-C 37; LDL-C 202	Atorvastatin 80 mg
	LDL-C 181	Atorvastatin 80 mg+ezetimibe 10 mg
	LDL-C 169	Atorvastatin 80 mg+ezetimibe 10 mg+niacin 1g
	LDL-C 160; pururitus	Atorvastatin 80 mg+ezetimibe 10 mg+cholestyramine 4–8g
	LDL-C 146–209

FH, familial hypercholesterolemia; CABG, coronary artery bypass graft; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol.

Notes

^{Conflict of Interest} The authors have no conflicts of interest to declare.

This article is based on the Symposium of Education Committee, Korean Society of Lipid and Atherosclerosis (Knowing and treating familial hypercholesterolemia right) held on May 26, 2018.

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