How Can We Improve the Diagnosis Rate of Familial Hypercholesterolemia by Amending Diagnosis Criteria?

Familial hypercholesterolemia (FH) is a genetic disease caused by mutations in genes affecting low-density lipoprotein (LDL) receptor (LDLR) activity, such as LDLR, proprotein convertase subtilisin/kexin type 9 (PCSK9), and apolipoprotein B (APOB). LDL particles are retained in the circulation due to impaired LDLR activity in FH patients. Very high LDL-C levels from birth place FH patients at very high risk for the development of coronary artery disease (CAD).¹ In the treatment of FH, it is very important to have an accurate diagnosis and start lipid-lowering therapy as early as possible to reduce lifetime LDL burden and prevent CAD.

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There are several diagnostic criteria used as standards for the diagnosis of FH, including the Dutch Lipid Clinical Network (DLCN) FH criteria,² the Simon-Broome diagnostic criteria, the Make Early Diagnosis to Prevent Early Death (MEDPED) criteria, and the 2017 Japan Atherosclerosis Society (JAS) FH criteria.^3,4 The DLCN FH criteria use a scoring system for items such as family history, personal history, clinical examination, LDL-C levels, and the presence of mutations in genes related to FH.² The DLCN FH criteria are useful and most widely used as inclusion criteria for clinical trials. However, it may be challenging to use DLCN criteria as a diagnostic tool in everyday clinical settings because of their complicated nature. Conversely, the 2017 JAS FH criteria contain only 3 items: LDL-C levels, the presence of xanthomas, and a family history of FH or premature CAD.³ The simple nature of the 2017 JAS FH criteria has made it possible for general practitioners or non-specialists to make an accurate diagnosis of FH. However, there has been no study comparing the 2017 JAS FH criteria and the DLCN FH criteria using Japanese FH patients.

In this issue of the Journal, Tada et al assessed the predictive values of the presence of pathogenic mutations of FH using the 2017 JAS and the DLCN FH criteria in the Kanazawa University cohort.⁵ Of the 680 subjects enrolled in the study, 175 had pathogenic mutations of FH. The sensitivity and specificity of the mutations in predicting FH were 0.863 and 0.956, respectively, which seems acceptable for diagnostic criteria. Five non-FH patients clinically diagnosed by the 2017 JAS FH criteria turned out to have FH mutations. Tada et al concluded that the 2017 JAS FH criteria are simple, easy to use, and have high sensitivity and specificity.⁵

Compared with other elements used in the FH diagnostic criteria, such as LDL-C and family history, the presence of tendon xanthoma has much higher specificity, with a score of 6 in the DLCN scoring system. Evaluation of tendon xanthoma in the 2017 JAS FH criteria is characterized by quantification of Achilles’ tendon thickness (ATT) using X-rays, which provides an accurate measurement of tendon xanthoma, making it possible to increase the sensitivity of the diagnosis compared with other criteria that have no objective quantification system. In the 2017 JAS FH criteria, a cut-off value for ATT of 9 mm was determined using a limited number of subjects (36 normal and 18 FH patients) in 1977 when statins were not available.⁶ Therefore, these cut-off values need to be re-evaluated using a larger number of FH patients whose LDL-C levels are better controlled by recent lipid-lowering drugs than 40 years ago. Tada et al calculated a cut-off value for ATT of 7.0 mm.⁵ In fact, ATT measurement requires an X-ray irradiator, which is not usually found in private clinics in Japan.

Recently, we evaluated ATT using ultrasonography (US), which is more commonly available in private clinics and does not involve exposure to X-rays.⁷ ATT quantification by US is considered to be more accurate because the outline of the Achilles’ tendon can be clearly distinguished (Figure). We evaluated ATT in 130 FH and 155 non-FH patients, as determined by molecular analysis.⁷ Using receiver operating characteristic (ROC) curve analysis, we found ATT cut-off values of 6.0 and 5.5 mm in males and females, respectively. Ultrasound devices are commonly used for the evaluation of atherosclerosis in the carotid arteries. Quantification of ATT may provide significant information regarding the development of atherosclerosis in FH because ATT reflects the lifetime LDL burden.⁸ We recently reported that softness of the Achilles’ tendon is an additional tool for the diagnosis of FH, which can be measured as an elasticity index using US.⁹

Figure.

Ultrasound appearance of the Achilles tendon in (A) a 77-year-pld patient with familial hypercholesterolemia (FH) and (B) a 70 year-old patient without FH.

FH is defined as having mutations in genes related to LDLR activity, inducing the retention of LDL in the blood circulation.¹ FH can definitely be diagnosed by genetic analysis, which is not included as an item for the diagnosis of FH in the 2017 JAS FH criteria, although it is recommended. One of the items in these criteria are “untreated” LDL-C levels (i.e., >180 mg/dL). However, data on untreated LDL-C levels are not always available because sometimes patients have already started lipid-lowering therapy and do not have untreated levels recorded.¹⁰ Even if a patient has not started lipid-lowering therapy, LDL-C levels will be lower than usual in acute coronary syndrome.¹¹ Another criterion, namely family history, sometimes cannot be obtained because of problems within the families, such as divorce. In order to make a definite diagnosis, the results of genetic analyses are quite useful because these do not change during the lifetime. The addition of genetic variants of PCSK9 to LDLR mutations was reported to identify a more severe form of FH, providing information regarding the expected prognosis.¹²

Finally, the sensitivity of the 2017 JAS FH criteria will increase with the re-evaluation of ATT and the addition of molecular diagnosis.

Disclosures

M.H.-S. holds stock in Liid Pharma, has received scholarship grants from Aegerion, Recordati, and Kaneka, and has received honoraria from Amgen, Astellas, and Sanofi. M.H.-S. is also a member of Circulation Journal’s Editorial Team.

IRB Information

This study was approved by the Ethics Committee of the National Cerebral and Cardiovascular Center (Approval no. M25-112).

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