A reassessment of the Japanese clinical diagnostic criteria of familial hypercholesterolemia in a hospital-based cohort using comprehensive genetic analysis

Hayato Tada,Hirofumi Okada,Akihiro Nomura,Atsushi Nohara,Soichiro Usui,Kenji Sakata,Masayuki Takamura,Masa-Aki Kawashiri

doi:10.1016/j.plabm.2020.e00180

Abstract

BackgroundClinical diagnostic criteria of familial hypercholesterolemia (FH) in Japan include LDL cholesterol ≥ 180 mg/dL, Achilles tendon thickness ≥ 9.0 mm, and family history. However, few data exist regarding its validation. Design and MethodsA series of 680 participants, with a mean LDL cholesterol of 175 mg/dL were enrolled at Kanazawa University Hospital between 2006 and 2018. All had full assessments of, LDL cholesterol, Achilles tendon X-rays, family history records, and genetic analysis of FH-associated genes (LDLR, APOB, and PCSK9). The area under the curve (AUC) of receiver operating characteristic (ROC) curve analysis predicting the presence of FH mutations by each clinical marker were assessed. ResultsThe optimal cutoff values predicting the presence of an FH-associated mutation were 181 mg/dL for LDL cholesterol and ≥7.0 mm for Achilles tendon thickness. AUCs predicting FH mutations were 0.827 for Achilles tendon thickness ≥9.0 mm, 0.889 for LDL cholesterol ≥180 mg/dL, and 0.906 for family history. If Achilles tendon thickness ≥7.0 mm was used as a clinical criterion, then 41 participants (6%) were newly diagnosed with FH and 86 (12%) were newly misclassified as FH. ConclusionsCurrent clinical diagnostic criteria of FH were validated in this cohort. We recommend considering a tentative diagnosis of “potential FH” if the Achilles tendon thickness is ≥ 7.0 mm and <9.0 mm rather than dismissing a diagnosis of FH.

Highlights

Familial hypercholesterolemia (FH; OMIM #143890) is characterized by a clinical triad of primary hyper-low-density lipoprotein (LDL)-cholesterolemia, tendon xanthomas, and premature coronary artery disease (CAD) [1]
Even though familial hypercholesterolemia (FH) is thought to be caused by deleterious mutations in genes associated with LDL metabolism such as LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9), and accumulation of LDL-raising single nucleotide polymorphisms [2], genetic testing is rarely used in clinical settings [3]
The LDL cholesterol value was determined by classical analysis of only LDLR gene mutations [8], Achilles tendon thickness was not determined based on a study through genetic analysis in FH patients [9]

Summary

Introduction

Familial hypercholesterolemia (FH; OMIM #143890) is characterized by a clinical triad of primary hyper-low-density lipoprotein (LDL)-cholesterolemia, tendon xanthomas, and premature coronary artery disease (CAD) [1]. The LDL cholesterol value was determined by classical analysis of only LDLR gene mutations [8], Achilles tendon thickness was not determined based on a study through genetic analysis in FH patients [9]. The study objective was to reassess the current Japanese FH criteria with comprehensive genetic analysis including the PCSK9 gene. Clinical diagnostic criteria of familial hypercholesterolemia (FH) in Japan include LDL cholesterol ! All had full assessments of, LDL cholesterol, Achilles tendon X-rays, family history records, and genetic analysis of FH-associated genes (LDLR, APOB, and PCSK9). Results: The optimal cutoff values predicting the presence of an FH-associated mutation were 181 mg/dL for LDL cholesterol and !7.0 mm for Achilles tendon thickness. AUCs predicting FH mutations were 0.827 for Achilles tendon thickness !9.0 mm, 0.889 for LDL cholesterol !180 mg/dL, and 0.906 for family history. We recommend considering a tentative diagnosis of “potential FH” if the Achilles tendon thickness is ! 7.0 mm and

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Conclusion