Impact of genetic defects on atherosclerosis in patients suspected of familial hypercholesterolaemia.

BACKGROUND: Among patients with severe hypercholesterolaemia and a family history of early cardiovascular disease, we assessed whether patients with mutations of low-density lipoprotein (LDL) receptor and apolipoprotein B genes related to familial hypercholesterolaemia (FH) have a different degree of atherosclerosis than those without such mutations. METHOD: In our lipid clinics, 273 patients were selected on the basis of a severe hypercholesterolaemia (cholesterol above 95th percentile) and a family history of early cardiovascular disease. By molecular genetic test, 122 patients were classified as FH. Atherosclerosis was evaluated by the ultrasonographic measurement of intima-media thickness (IMT) in the carotid and femoral arteries. RESULT: Despite the fact that non-FH individuals had a higher prevalence of obesity, hypertension, diabetes and hypertriglyceridaemia, FH individuals had significantly greater carotid and femoral IMT than non-FH patients: difference between carotid and femoral IMT, respectively, 0.19 mm (95% CI, 0.08-0.29; P < 0.001) and 0.20 mm (95% CI, 0.09-0.35; P = 0.001), respectively. These differences remained statistically significant after adjustment for the various risk factors as well as in sub-analysis restricted to the patients with LDL-cholesterol between 240 and 300 mg dL-1 (range with similar distribution in the two groups). When classified according to the severity of their mutations, FH individuals with null LDL receptor allele tended to have thicker carotid IMT than FH individuals carrying the LDL receptor-defective allele. CONCLUSION: Among patients with severe hypercholesterolaemia and a family history of early cardiovascular disease, the presence of a genetically ascertained FH is associated with a higher degree of atherosclerosis. This suggests that molecular genetic identification of FH may be helpful to evaluate better the coronary heart disease risk in these patients.

The use of Achilles tendon ultrasonography for the diagnosis of familial hypercholesterolemia.

Differentiating FH from other causes of hypercholesterolemia has important clinical and therapeutic implications but is often not possible by standard clinical criteria. As accumulation of cholesterol in tendon is generally considered as pathognomonic of FH, we evaluated the sensitivity and specificity of clinical and ultrasonographic tendon characteristics using the data of 127 genetically ascertained FH and 160 controls with various lipid profiles. Upon clinical examination, none of the controls and 29% of FH individuals (17% FH women and 38% FH men) presented with xanthomata in Achilles tendons, but no female and only 6% of male FH patients also showed xanthomata in the extensor tendon of the hand. Amongst all possible quantitative parameters (thickness, breadth, section and roundness) of Achilles tendon (AT) measured by ultrasonography, the thickness presented the best receiver operating curves. AT thickness above 5.8 mm was the most useful threshold for diagnosis of FH, procuring sensitivity of 75% and specificity of 85%. Analysis of variation of AT thickness with age and sex indicated that this clinical criterion performed better in females older than 45 and in males under 45. In patients carrying the APOB-R3500Q mutation, AT-thickness appeared significantly less important compared with those carrying LDLR mutations. In conclusion, this study recommends identification of possible FH individuals amongst hypercholesterolemic patients using a criteria of AT-thickness over 5.8 mm eventually associated with a specific genetic test for APOB-R3500Q mutation.