Early diagnosis is important in familial hypercholesterolemia (FH), a highly atherogenic
condition, but internationally agreed clinical diagnostic criteria are lacking. Genetic
testing for low-density lipoprotein (LDL) receptor (LDLR) and apolipoprotein B (APOB)
gene defects is the preferable diagnostic method, but the best phenotype indication
to proceed with genetic diagnosis has not been established. The aim of this study
was to assess the predictive and accuracy values of standard diagnostic criteria for
detecting disease-causing mutations in 825 subjects with clinical FH aged ≥14 years
from 3 lipid clinics in Spain. All subjects underwent thorough genetic testing for
the detection of LDLR and APOB defects using the Lipochip platform. FH-causing mutations
were detected in 459 subjects (55.6%). By logistic regression analysis, familial or
personal history of tendon xanthoma (TX) and LDL cholesterol were strongly associated
with genetic diagnosis (p <0.005, R2 = 0.41). In subjects without familial or personal histories of TX, the diagnostic
criteria for FH of the Make Early Diagnosis to Prevent Early Deaths (MEDPED) project,
based on age-specific LDL cholesterol thresholds, showed sensitivity of 72.4%, specificity
of 71.1%, and accuracy of 71.6%. LDL cholesterol ≥190 mg/dl in subjects with familial
or personal histories of TX and ≥220, ≥225, and ≥235 mg/dl in those without such histories
aged <30, 30 to 39, and ≥40 years, respectively, showed sensitivity of 91.1%, specificity
of 71.1%, and accuracy of 74.2% for a positive genetic diagnosis. This new set of
diagnostic criteria for FH was validated in an independent group of 440 subjects from
6 additional Spanish lipid clinics. In conclusion, TX and age-adjusted LDL cholesterol
cut-off values have the highest value for clinical diagnosis and indication of genetic
testing in FH.
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Article info
Publication history
Published online: August 29, 2008
Accepted:
June 17,
2008
Received in revised form:
June 17,
2008
Received:
March 12,
2008
Footnotes
This study was supported by grants PI05/0247, PI06/0365, PI06/1402 (Fondo de Investigaciones Sanitarias de la Seguridad Social) and RTIC C06/01 (Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares) from the Spanish Ministry of Health, Madrid, Spain, and grant SAF2005-07042 from the Spanish Ministry of Education and Science, Madrid, Spain.
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© 2008 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
