Abstract
Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by marked hypercholesterolemia, tendon xanthomas and premature coronary heart disease (CHD). It is generally accepted that FH is a very atherogenic disease, since homozygous FH is often accompanied by myocardial infarction before age 30 and even in its heterozygous form CHD becomes manifest at an earlier age than in normal subjects. However, serum cholesterol levels in patients with heterozygous FH are not always parallel to the severity of CHD and there must be other factors affecting the development of CHD in FH. Eighty-three subjects with heterozygous FH aged over 30 years were included in this study. The incidence of CHD became higher with their age in both sexes, and especially in female patients CHD became manifest over 50 years of age. Patients were subdivided into two groups in each sex with and without CHD, and we then compared between each group as to LDL receptor activities, serum lipids and lipoproteins, as well as clinical parameters such as Achilles tendon thickness (ATT), blood pressure and the incidence of corneal arcus, xanthelasma and tuberous xanthoma.
There was no significant difference in serum total cholesterol levels between two groups with and without CHD in both sexes, whereas serum HDL-cholesterol levels were significantly lower and atherogenic indices significantly higher in both sexes in CHD (+) group than in CHD (-) group. Serum triglyceride levels were higher in CHD (+) group especially in males and ATT tended to be thicker in CHD (+) group in both sexes. There was no significant difference between the two groups in blood pressure and the incidence of xanthelasma and corneal arcus, although tuberous xanthomas were more frequently seen in CHD (+) group.
In fifty-one subjects (30 males and 21 females), we determined LDL receptor activities of skin fibroblasts according to the method of Goldstein et al. Even in FH-heterozygotes, there were wide variations in the LDL receptor activities, which negatively correlated with the level of serum total-and LDL-cholesterol levels. There was a tendency that LDL receptor activities were relatively lower in CHD (+) group than in CHD (-) group, but there was some cases with CHD whose LDL receptor activities were relatively high.
We also referred to atypical two cases of FH with elevated serum cholesterol levels and Achilles tendon xanthomas, and these traits were considered to be inherited in this family. However, LDL receptor activities (binding, internalization and degradation) of these cases were higher than those of normal controls in several determinations and they showed no clinical signs of CHD. Abnormalities in LDL receptor proteins have recently been classified by Goldstein & Brown at a molecular level, therefore the impaired locus of these cases must further be elucidated, but at present we include these cases in the category of FH.
