Key words :Familial hypercholesterolemia, Acute coronary syndrome, Xanthoma, Japan Atherosclerosis Society guideline, Dutch Lipid Clinic Algorism
The Japan Atherosclerosis Society has proposed guidelines for the diagnosis of familial hypercholesterolemia (FH) (JASG) in 20121) and has published the renewed version in 20182). According to the guidelines, FH is identified by two of three major symptoms of high amounts of low-density lipoprotein (LDL)-cholesterol (≥ 180 mg/dL), family history of FH/premature coronary artery diseases (CAD), and tendon/skin xanthomas as Achilles tendon thickness (ATT) ≥ 9 mm1). It is designed to encourage the identification of FH patients in the general practice2). On the other hand, the Dutch Lipid Clinic Algorism (DLCA)3) is widely used for FH diagnosis in the European Union countries and else being based on a scoring system by family and clinical history, physical examination, and LDL cholesterol for the levels of certainty in diagnosis.
FH is a hereditary disorder in the receptor-mediated cellular uptake of LDL resulting in a marked elevation of plasma LDL and a high risk of CAD2). Causative mutations are predominantly in the LDL receptor gene but also in other related genes, such as apoB, PCSK9, or ARH2). Altogether, the prevalence of the FH allele is estimated to be 0.2–0.5% in the general population regardless of the ethnic background. Since more than one-half of the untreated FH is likely to develop premature CAD, a substantial portion of the CAD patients are from the FH population. A lower incidence of CAD in Japan than the West may make this contribution higher. It is therefore important to compare the FH contribution to CAD between Japan and the West to estimate the impact of FH management in our public health. The guidelines help in the survey of FH that is generally underdiagnosed in routine practice.
We investigated the prevalence of FH by using JASG and DLCA in consecutive 141 acute coronary syndrome (ACS) patients who visited Ichinomiya Nishi Hospital from May 2010 to December 2017. Informed consent was obtained from all the patients. The hospital with 464 beds and visited daily by some 1000 outpatients covers suburban-rural community of Ichinomiya city with a population of 390,000 as one of the 3 major hospitals of similar capacity. Plasma cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglyceride levels were measured at the institutional clinical laboratory, and LDL cholesterol was determined using a homogeneous assay method standardized for the Friedewald procedure. ATT was measured on X-ray films as previously described4). The study protocol was approved by the institutional ethics committee in accordance with Ethical Guidelines for Epidemiological Research, and Ethical Guidelines for Medical and Health Research Involving Human Subjects by Ministry of Health, Labor and Welfare of Japan.
Patients backgrounds are shown in the supplementary tables. The prevalence of FH by JASG and DLCA in this ACS population is described in Table 1. Tendinous xanthoma is one of the major symptoms in these guidelines but not quantitatively defined in DLCA. Arbitrary definitions were therefore introduced as ATT ≥ 9 mm following JASG and as ATT ≥ 12 mm to match its apparent palpable sign in physical examination. According to JASG, 7 patients met the criteria of family history, 21 patients met the ATT criteria, and 13 met by LDL cholesterol criteria (Supplementary Table 3). Accordingly, 6 patients were identified as FH patients (4.3%). The prevalence of FH was much higher in the group aged < 60 years (15.4%) than the other age group aged ≥ 60 years (1.7%; p = 0.002). DLCA by using ATT ≥ 9 mm showed a definite FH of 2.8% overall with 11.5% under 60 years of age and 0.9% at over 60 years (p = 0.003). Definite/probable FH was 14.8% overall, with 23.1% under 60 years of age and 13.0 at/over 60 years (p = 0.194). With ATT ≥ 12 mm, the overall definite FH was 1.4%, with 3.8% under 60 years of age and 0.9% at/over 60 years (p = 0.246). Consequently, under this definition, the definite/probable FH was 4.3% overall, with 11.5% in those < 60 years of age and 2.6% in the older group (p = 0.042).
Table 1. Prevalence of FH in the ACS patients (N, %) based on diagnosis by JASG and by DLCA using ATT ≥ 9 mm and ATT ≥ 12 mm as categories Definite and Definite/Probable, in all ages and in Age groups under 60 year-old and the group of 60 or above.
| Age group | All | < 60 | 60 ≤ | p |
|---|---|---|---|---|
| N | 141 | 26 | 115 | |
| JASG | 6 (4.3) | 4 (15.4) | 2 (1.7) | < 0.002 |
| DLCA, ATT ≥ 9mm | ||||
| Definite | 4 (2.8) | 3 (11.5) | 1 (0.9) | 0.003 |
| Definite/Probable | 21 (14.9) | 6 (23.1) | 15 (13.0) | 0.194 |
| DLCA, ATT ≥ 12mm | ||||
| Definite | 2 (1.4) | 1 (3.8) | 1 (0.9) | 0.246 |
| Definite/Probable | 6 (4.3) | 3 (11.5) | 3 (2.6) | 0.042 |
Categorical variables were compared using the chi-square test or Fisher's exact test. A value of P < 0.05 is considered statistically significant between the age groups
Supplementary Table 3. Patients Characteristics by Age groups (n, %, unless otherwise defined).
| Age group, | < 60, | 60 ≤ < 70, | 70 ≤ < 80, | ≤ 80, |
|---|---|---|---|---|
| N | N = 26 | N = 42 | N = 45 | N = 28 |
| Age, Ave ± SE (y) | 50.3 ± 6.0 | 65.5 ± 2.8 | 74.7 ± 2.8 | 85.0 ± 3.0 |
| Female | 2 (7.7%) | 9 (21.4%) | 16 (35.6%) | 9 (32.1%) |
| Diabetes Mellitus | 8 (30.1%) | 20 (47.6%) | 22 (48.9%) | 8 (28.6%) |
| Dyslipidemia | 22 (84.6%) | 33 (78.6%) | 28 (62.2%) | 12 (42.9%) |
| Hypertension | 16 (61.5%) | 26 (61.9%) | 35 (77.8%) | 21 (75.0%) |
| Smoking | 24 (92.3%) | 31 (73.8%) | 23 (51.1%) | 14 (50.0%) |
| Acute Coronary Syndrome (ACS) | 0 (0.0%) | 2 (4.8%) | 0 (0.0%) | 1 (3.6%) |
| Effort Angina | 1 (3.8%) | 1 (2.4%) | 0 (0.0%) | 0 (0.0%) |
| Cerebral Infarction | 0 (0.0%) | 4 (9.5%) | 4 (8.9%) | 6 (21.4%) |
| Cerebral Hemorrhage | 0 (0.0%) | 0 (0.0%) | 1 (2.2%) | 0 (0.0%) |
| Family history in 2nd deg. relatives | 9 (34.6%) | 11 (26.3%) | 13 (28.9%) | 5 (17.9%) |
| Male relative with CAD under 50 yo | 2 (7.7%) | 1 (2.4%) | 1 (2.2%) | 1 (3.6%) |
| Female relative with CAD under 60 yo | 1 (3.8%) | 1 (2.4%) | 0 (0.0%) | 0 (0.0%) |
| Relative with FH | 0 (0.0%) | 1 (2.4%) | 0 (0.0%) | 0 (0.0%) |
| Height (m) | 1.69 ± 0.09 | 1.63 ± 0.10 | 1.57 ± 0.08 | 1.53 ± 0.09 |
| Body weight (kg) | 79.0 ± 15.9 | 62.6 ± 12.3 | 56.3 ± 9.5 | 52.6 ± 11.2 |
| Body mass index (kg/m2) | 27.6 ± 5.1 | 23.6 ± 3.8 | 22.8 ± 2.7 | 22.3 ± 3.8 |
| Systolic blood pressure (mmHg) | 143 ± 27 | 140 ± 26 | 141 ± 34 | 130 ± 39 |
| Diastolic blood pressure (mmHg) | 91 ± 17 | 83 ± 17 | 79 ± 14 | 72 ± 21 |
| Heart Rate (bpm) | 76 ± 17 | 74 ± 18 | 79 ± 23 | 77 ± 33 |
| Achilles' Tendon Thickness (mm) | 8.1 ± 2.7 | 7.0 ± 1.2 | 7.9 ± 2.9 | 7.4 ± 1.5 |
| Total cholesterol (mmol/L) | 5.37 ± 1.42 | 4.94 ± 1.18 | 5.24 ± 1.77 | 4.44 ± 0.92 |
| LDL cholesterol (mmol/L) | 3.68 ± 1.32 | 3.40 ± 1.05 | 3.24 ± 1.45 | 2.63 ± 0.80 |
| HDL cholesterol (mmol/L) | 1.14 ± 0.35 | 1.08 ± 0.31 | 1.16 ± 0.36 | 1.21 ± 0.36 |
| Triglyceride (mmol/L) | 2.13 ± 2.23 | 1.47 ± 1.10 | 1.60 ± 1.49 | 1.11 ± 0.96 |
| Hba1c | 5.9 ± 0.7 | 6.5 ± 1.5 | 6.3 ± 1.1 | 6.2 ± 0.9 |
| eGFR (mL/min/1.73 m2) | 76.9 ± 17.4 | 68.0 ± 21.2 | 61.6 ± 20.4 | 52.1 ± 22.4 |
| LDL-C (mg/dL) > 180 mg/dl | 6 (23.1%) | 5 (11.9%) | 2 (4.4%) | 0 (0.0%) |
| Family History | 3 (11.5%) | 2 (4.8%) | 1 (2.2%) | 1 (3.6%) |
| ATT(mm) < 9.0 mm | 6 (23.1%) | 3 (7.1%) | 7 (15.6%) | 5 (17.9%) |
| Familial Hypercholesterolemia by JASG | 4 (15.4%) | 1 (2.3%) | 1 (2.2%) | 0 (0.0%) |
Data are expressed as mean ± SD for continuous variables and as numbers (%) for categorical variables
Fig. 1 compares JASG and DLCA in finding FH in this cohort groups by showing the prevalence of FH in each 4-age group of under 60 years, 60 to 69 years, 70 to 79 years, and 80 years and higher. To make comparison easier, the results by DLCA were represented by “definite” with ATT ≥ 9 mm and “probable/definite” with ATT ≥ 12 mm. JASG and “definite” by DLCA with ATT ≥ 9 mm demonstrated more FH in the younger age group, but the other did not show significant difference.
Fig. 1.
Prevalence of familial hypercholesterolemia patients in each age groups of those with acute coronary syndrome
A total of 141 ACS patients are divided into those aged < 60 years (n = 26), 60 ≤ those < 70 (n = 42), 70 ≤ those < 80 (n = 45) and 80 ≤ those (n = 28). Each age group is characterized in Supplementary Table 3. JASG indicates FH diagnosed by JASG, ATT ≥ 9 shows FH identified as definite by DLCA by using ATT ≥ 9 mm for tendon xanthoma criteria, and DLCA ATT ≥ 12 mm shows FH as definite/probable by DLCA with ATT ≥ 12 mm for tendon xanthoma. Data were analyzed using the 2-tailed Student t test for two groups, as ** indicates p < 0.01 and * indicates p < 0.05 against the age group of under 60 years.
A Switzerland study by DLCA identified 1.6% and 4.8% of probable/definite FH among ACS in all ages and those under 60 years of age, respectively5). A Danish study found a probable/definite FH of 2.0% and 7.0% in those with the first myocardial infarction of all ages and under 60 years of age, respectively6, 7). In contrast, EUROASPIRE covering 7044 coronary patients from 24 European countries found a more definite/probable FH of 8.3% in all ages and 15.4% and 5.1% for under and above 60 years, respectively8). Similar reports from China demonstrated a contribution of FH to CAD by adopting the DLCA definite/probable criteria, with 3.9% for all ages and 7.1% for under 60 years9). The higher prevalence of FH in ACS patients in the younger age group is consistent throughout these reports, while inconsistency may exist in the rate of FH contribution.
Ohmura, et al. reported that FH was 5.7% and 7.8% in all ages and under 60, respectively, using JASG among 359 Japanese ACS patients from 5 major urban hospitals10), which was higher than those of Swiss and Danish studies using DLCA. Our data using JASG among 141 ACS patients in a single community hospital in Japan demonstrated an FH of 4.3% in all and 15.4% in under 60 years of age, largely consistent with the previous report10). However, the application of DLCA to the same cohort yielded diverse data. The critical problem in DLCA appears to be the high score given to tendon xanthoma without clear definition. We may need more effort for harmonization and standardization among the guidelines for a reliable international comparison of FH contribution to public health. The most recent publication by Harada-Shiba, et al. found FH as 2.7 % among overall 1944 Japanese ACS patients11). It is of interest to analyze their data in a comparable manner to ours including grouping by age and application of DLCA.
The diagnosis of FH in general practice is not straightforward even with currently proposed guidelines. Genetic analysis does not cover all aspects, and its clinical features are diverse. Family history information is very important but inevitably overlooked in general practice. The common use of statin also causes difficulty and confuses masking the LDL cholesterol level of FH patients. Twenty-six percent of the patients in this study indeed took statins before the first visit. This may be beneficial for the patients but sometimes underdosed for FH. We always consider the possibility of underestimation of FH in such studies.
Acknowledgments
We thank Dr. Takuya Maeda, Hiroki Ishihara, Kazuhiro Dan, Masanori Teramura, Kei Ichihashi, Yuya Takahashi, Daichi Tsuzura, Akira Shinoda and Masato Fujii for contribution to acquisition of the data.
Footnotes
Nobukiyo Tanaka at nobukiyo282000@yahoo.co.jp is responsible for collecting and primary analysis of the data.
Sources of Funding
Health, Labour and Welfare Sciences Research Grant for Research on Rare and Intractable Diseases (SY).
Disclosures
None.
Supplementary Table 1. Patients Characteristics.
| N = 141 | |
|---|---|
| Age (y) | 69.5 ± 11.9 |
| Female (n, %) | 36 (25.5%) |
| Diabetes Mellitus (n,%) | 58 (41.1%) |
| Dyslipidemia (n, %) | 95 (67.4%) |
| Hypertension (n, %) | 98 (70.0%) |
| Smoking (n, %) | 92 (65.2%) |
| Acute Coronary Syndrome (ACS) | 3 (2.1%) |
| Age of initial ACS (y) | 69.2 ± 12.4 |
| Effort Angina | 2 (1.4%) |
| Cerebral Infarction | 14 (9.9%) |
| Cerebral Hemorrhage | 1 (0.7%) |
| Family history within second degree relatives (n, %) | 38 (27.1%) |
| Male relative with CAD under 50 yrs old (n, %) | 5 (4.0%) |
| Female relative with CAD under 60 yrs old (n, %) | 2 (1.5%) |
| Relative with Familial Hypercholesterolemia (n, %) | 1 (0.7%) |
| Height (m) | 1.60 ± 0.10 |
| Body weight (kg) | 61.6 ± 15.0 |
| Body mass index (kg/m2) | 23.8 ± 4.2 |
| Systolic blood pressure (mmHg) | 139 ± 32 |
| Diastolic blood pressure(mmHg) | 81 ± 18 |
| Heart Rate (bpm) | 77 ± 23 |
| Achilles' Tendon Thickness (mm) | 7.6 ± 2.2 |
| Total cholesterol (mmol/L) | 5.02 ± 1.42 |
| LDL cholesterol (mmol/L) | 3.25 ± 1.24 |
| HDL cholesterol (mmol/L) | 1.14 ± 0.34 |
| Triglyceride (mmol/L) | 1.56 ± 1.49 |
| Hemoglobin a1c (%) | 6.4 ± 1.2 |
| eGFR (mL/min/1.73 m2) | 64.4 ± 21.9 |
eGFR was estimated as 194 serum creatinine−1.094 × age−0.287 for men, and eGFR of men × 0.739 for women according to the estimate equation proposed by the Japanese Society of Nephrology.
Supplementary Table 2. Oral Medications (N, %).
| N = 141 | |
|---|---|
| Aspirin | 22 (15.6%) |
| Thienopyridine | 12 (8.5%) |
| Anticoaglant | 3 (2.1%) |
| Nicorandil | 4 (2.8%) |
| Statin | 36 (25.5%) |
| Fibrate | 5 (3.5%) |
| EPA | 3 (2.1%) |
| Ezetimibe | 0 (0.0%) |
| Nicotinate | 1 (0.7%) |
| ACE inhibitor | 7 (5.0%) |
| ARB | 43 (30.5%) |
| βblocker | 7 (5.0%) |
| Calcium blocker | 56 (39.7%) |
| Diuretics | 11 (7.8%) |
| αglucosidase inhibitor | 12 (8.5%) |
| Biganide | 11 (7.8%) |
| Thiazolidine | 9 (6.4%) |
| SGLT2 inhibitor | 2 (1.4%) |
| DPP4 inhibitor | 14 (9.9%) |
| Incletin | 1 (0.7%) |
| Sulfonylureas and glinides | 10 (7.1%) |
| Insulin | 5 (3.5%) |
References
- 1). Harada-Shiba M, Arai H, Oikawa S, Ohta T, Okada T, Okamura T, Nohara A, Bujo H, Yokote K, Wakatsuki A, Ishibashi S, Yamashita S: Guidelines for the management of familial hypercholesterolemia. J Atheroscler Thromb, 2012; 19: 1043-1060 [DOI] [PubMed] [Google Scholar]
- 2). Harada-Shiba M, Arai H, Ishigaki Y, Ishibashi S, Okamura T, Ogura M, Dobashi K, Nohara A, Bujo H, Miyauchi K, Yamashita S, Yokote K: Guidelines for diagnosis and treatment of familial hypercholesterolemia 2017. J Atheroscler Thromb, 2018; 25: 751-770 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3). https://www.athero.org.au/fh/wp-content/uploads/Dutch-Lipid-Clinic-Network-Score2.pdf:
- 4). Mabuchi H, Ito S, Haba T, Ueda K, Ueda R: Discrimination of familial hypercholesterolemia and secondary hypercholesterolemia by achilles' tendon thickness. Atherosclerosis, 1977; 28: 61-68 [DOI] [PubMed] [Google Scholar]
- 5). Nanchen D, Gencer B, Auer R, Raber L, Stefanini GG, Klingenberg R, Schmied CM, Cornuz J, Muller O, Vogt P, Juni P, Matter CM, Windecker S, Luscher TF, Mach F, Rodondi N: Prevalence and management of familial hypercholesterolaemia in patients with acute coronary syndromes. Eur Heart J, 2015; 36: 2438-2445 [DOI] [PubMed] [Google Scholar]
- 6). Mortensen MB, Kulenovic I, Klausen IC, Falk E: Familial hypercholesterolemia among unselected contemporary patients presenting with first myocardial infarction: Prevalence, risk factor burden, and impact on age at presentation. J Clin Lipidol, 2016; 10: 1145-1152.e1141 [DOI] [PubMed] [Google Scholar]
- 7). Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG: Familial hypercholesterolemia in the danish general population: Prevalence, coronary artery disease, and cholesterol- lowering medication. J Clin Endocrinol Metab, 2012; 97: 3956-3964 [DOI] [PubMed] [Google Scholar]
- 8). De Backer G, Besseling J, Chapman J, Hovingh GK, Kastelein JJ, Kotseva K, Ray K, Reiner Z, Wood D, De Bacquer D, Investigators E : Prevalence and management of familial hypercholesterolaemia in coronary patients: An analysis of euroaspire iv, a study of the european society of cardiology. Atherosclerosis, 2015; 241: 169-175 [DOI] [PubMed] [Google Scholar]
- 9). Li S, Zhang Y, Zhu CG, Guo YL, Wu NQ, Gao Y, Qing P, Li XL, Sun J, Liu G, Dong Q, Xu RX, Cui CJ, Li JJ: Identification of familial hypercholesterolemia in patients with myocardial infarction: A chinese cohort study. J Clin Lipidol, 2016; 10: 1344-1352 [DOI] [PubMed] [Google Scholar]
- 10). Ohmura H, Fukushima Y, Mizuno A, Niwa K, Kobayashi Y, Ebina T, Kimura K, Ishibashi S, Daida H, Research Committee on Primary Hyperlipidemia of the Ministry of H, Welfare of J : Estimated prevalence of heterozygous familial hypercholesterolemia in patients with acute coronary syndrome. Int Heart J, 2017; 58: 88-94 [DOI] [PubMed] [Google Scholar]
- 11). Harada-Shiba M, Ako J, Arai H, Hirayama A, Murakami Y, Nohara A, Ozaki A, Uno K, Nakamura M: Prevalence of familial hypercholesterolemia in patients with acute coronary syndrome in japan: Results of the explore-j study. Atherosclerosis, 2018; 277: 362-368 [DOI] [PubMed] [Google Scholar]