Physical signs and atherosclerotic cardiovascular disease in familial hypercholesterolemia: the HELLAS-FH Registry

J Cardiovasc Med (Hagerstown). 2024 May 1;25(5):370-378. doi: 10.2459/JCM.0000000000001612. Epub 2024 Mar 19.


Aims: Three physical signs, namely tendon xanthomas, corneal arcus and xanthelasma, have been associated with heterozygous familial hypercholesterolemia (heFH). The prevalence and clinical significance of these signs are not well established among contemporary heFH individuals. This study explored the frequency as well as the association of these physical signs with prevalent atherosclerotic cardiovascular disease (ASCVD) in heFH individuals.

Methods: Data from the Hellenic Familial Hypercholesterolemia Registry were applied for this analysis. The diagnosis of heFH was based on the Dutch Lipid Clinic Network Score. Multivariate logistic regression analysis was conducted to examine the association of heFH-related physical signs with prevalent ASCVD.

Results: Adult patients ( n = 2156, mean age 50 ± 15 years, 47.7% women) were included in this analysis. Among them, 14.5% had at least one heFH-related physical sign present. The prevalence of corneal arcus before the age of 45 years was 6.6%, tendon xanthomas 5.3%, and xanthelasmas 5.8%. Among physical signs, only the presence of corneal arcus before the age of 45 years was independently associated with the presence of premature coronary artery disease (CAD). No association of any physical sign with total CAD, stroke or peripheral artery disease was found. Patients with physical signs were more likely to receive higher intensity statin therapy and dual lipid-lowering therapy, but only a minority reached optimal lipid targets.

Conclusion: The prevalence of physical signs is relatively low in contemporary heFH patients. The presence of corneal arcus before the age of 45 years is independently associated with premature CAD.

MeSH terms

  • Adult
  • Aged
  • Arcus Senilis* / diagnosis
  • Arcus Senilis* / epidemiology
  • Arcus Senilis* / etiology
  • Atherosclerosis* / epidemiology
  • Cardiovascular Diseases* / epidemiology
  • Coronary Artery Disease* / complications
  • Coronary Artery Disease* / etiology
  • Female
  • Heterozygote
  • Humans
  • Hypercholesterolemia* / complications
  • Hyperlipoproteinemia Type II* / complications
  • Hyperlipoproteinemia Type II* / diagnosis
  • Hyperlipoproteinemia Type II* / drug therapy
  • Lipids
  • Male
  • Middle Aged
  • Registries
  • Xanthomatosis* / complications
  • Xanthomatosis* / etiology


  • Lipids