Exploration Continues

See article vol. 32: 23-33

Familial hypercholesterolemia (FH) is an autosomal dominant inherited metabolic disorder caused by mutations in the low-density lipoprotein (LDL) receptor or related molecule genes. It is characterized by elevated LDL cholesterol (LDL-C) levels from birth, xanthomas including Achilles tendon thickening, and premature coronary artery disease (CAD).

If FH remains untreated, there is a significantly higher risk of CAD, but early diagnosis and appropriate treatment can delay CAD onset, making early diagnosis essential. However, the diagnosis rate is low¹⁾.

There are several reasons why the clinical diagnosis of FH has been difficult. For instance, the drop in LDL cholesterol levels during the acute phase of acute coronary syndromes (ACS) (especially acute myocardial infarction)²⁾ and the previous definition of Achilles tendon thickening of 9 mm or more for both men and women in the FH diagnostic criteria (2017 edition) of the Japan Atherosclerosis Society³⁾, which was lacking in sensitivity. In this regard, a prospective observational study on lipid risk and control in patients with acute coronary syndrome in Japan, EXPLORE J (Exploration into the lipid management and persistent risk in patients hospitalized for acute coronary syndrome in Japan) study, reported that the FH diagnostic criteria (2017 version) were not sensitive enough to detect genetically diagnosed FH⁴⁾. Also, our study of 2017, which proposed cutoff values using ultrasound for the measurement of Achilles tendon thickness and diagnosis of FH, found that the cutoff value for diagnosis of FH using radiography (＞9 mm for both sexes) had very high specificity but low sensitivity⁵⁾.

In a study to address this issue, Achilles tendon thicknesses of 986 patients, including 485 patients with genetically diagnosed FH, were measured by radiographic methods, which resulted in the proposal of the new cutoff values of 8.0 mm or more for men and 7.5 mm or more for women⁶⁾. These cutoff values were adopted in the 2022 edition of the FH diagnostic criteria⁷⁾.

In this issue of the Journal, Takeji et al. examined the usefulness of the 2022 version of the FH diagnostic criteria for detecting FH in patients with ACS as a sub-analysis of the EXPLORE J study⁸⁾. Although this resulted in increasing the sensitivity of the definition of Achilles tendon thickening and achieved a higher diagnostic rate, the rate of diagnosis for patients with pathological variants determined by genetic testing was still only 8%. Probably the most significant cause of the diagnostic rate remaining so low was temporarily decreased LDL-C levels in patients with ACS.

There are several types of screening for FH. A good sequence of testing in universal or cascade screening uses high LDL-C as an entry point, followed by Achilles tendon thickening, family history, and, if possible, genetic testing. It should however be emphasized that LDL-C values are not always a suitable entry point for opportunistic screening of patients with ACS. In the present study, the mean ages of the probable and definite FH groups were 59.9 years and 61.0 years, respectively. I therefore believe that patients of under 60 years with ACS should proceed to the next step for FH diagnosis (measurement of Achilles tendon thickness and family history taking) regardless of LDL-C level (Fig.1). In addition, considering the younger age of onset of ACS and the difficulty of obtaining a family history, genetic testing will become increasingly important in diagnosing FH in ACS patients. This is because genetic testing is beneficial in the diagnosis and treatment of an individual with FH and in the screening and treatment of family members.

Fig.1. LDL-C levels may not be a determining factor in finding FH in young ACS patients

ACS: acute coronary syndromes, LDL-C: low-density lipoprotein cholesterol

I also believe that when family history is obtained from ACS patients, family history of FH should be separated from that of ACS. FH is not necessarily the only family line with frequent myocardial infarction. In my experience, the susceptibility to ACS varies among family members with the same pathogenic mutation in the FH-related gene.

The radiographic method has a weakness in measuring the Achilles tendon thickness, which is that the thickness may be overestimated due to twisted attachment of the Achilles tendon to the calcaneus⁹⁾. Specificity is reduced when Achilles tendon twist is significant in non-FH. Therefore, the cutoff values for ultrasonography (6.0 mm or more for men and 5.5 mm or more for women) were also added to the diagnostic criteria (2022 edition). Future research on the clinical significance of measuring Achilles tendon thickness by ultrasound in patients with ACS and the appropriateness of the cutoff value is awaited.

Exploration into diagnostic criteria enabling efficient detection of FH among ACS patients will continue.

Disclosures

Masatsune Ogura has received lecture fees from Amgen, Ultragenyx Japan, and Kowa.

Funding

This work is supported by a Labor and Welfare Sciences Research Grant for Research on Rare and Intractable Diseases (24FC1012).

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