Clinical and Biochemical Studies on Hyper-HDL₂-cholesterolemia Associated with Juvenile Corneal Opacity

Abstract

We recently discovered two homozygous cases of hyper-HDL₂-cholesterolemia associated with premature corneal opacities. Patient 1 is a 55-year-old man, whose serum HDL-cholesterol levels were much elevated to -140mg/dl, while serum total cholesterol was only slightly increased and serum triglyceride moderately reduced. Serum levels of apolipoprotein (apo) A-I and E were also elevated. Patient 2 is a 58-year-old man whose serum HDL-cholesterol was also much increased to 130-169mg/dl. The lipid and lipoprotein patterns of these patients were closely similar by ultracentrifugal analysis and the increase of HDL-cholesterol was attributed solely to the enrichment of cholesteryl ester (CE) in HDL₂ fraction (1.063<d<1.125g/ml). The trait was considered to be inherited in the family of Patient 2. In postheparin plasma, LPL activities were increased in these patients, whereas H-TGL showed reduced activities. In order to elucidate the mechanism of accumulation of CE in HDL₂, we examined CE net transfer rate according to the modified method of Fielding et al. In control subjects there was a net mass transfer of CE from HDL to VLDL and LDL after a 1hr's incubation with DTNB at 37°C, while in both cases there was a net transfer of CE in the opposite direction leading to the accumulation of CE in HDL.
We also examined the effect of probucol on the lipoprotein and apoprotein levels of these patients. Probucol reduced serum levels of HDL-cholesterol, apo A-I and apo E parallel to the reduction of serum total cholesterol. The decrease of HDL-cholesterol was largely due to the reduction of cholesterol in HDL₂ fraction. Examination of patients' sera by HPLC disclosed that large HDL₂ particles became smaller to almost normal sizes after the treatment with probucol and that the change was proved to be reversible after stopping administration of the drug.
We also examined CE net transfer rate after treatment with probucol, and found that the reversion of CE net transfer was normalized in both cases after the therapy. We therefore conclude that abnormalities in CE net transfer might be involved in the pathogenesis of hyper-HDL₂-cholesterolemia.