Increased urinary excretion of glycosphingolipids in familial hypercholesterolemia

The content of glycosphingolipids (GSL) was studied in the urinary sediments (24-hr specimens) from seven normal subjects, a patient with Fabry's disease, and five homozygotes with familial hypercholesterolemia (FH). Normal urinary sediments contained very small amounts of GalCer, GlcCer, GaOse₂Cer, LacCer, GbOse₃Cer, and GbOse₄(er. In Fabry urinary sediment, the levels (nmole glucose/24hr) of GaOse₂Cer and of GbOse₃Cer were 389 and 550, respectively. In urinary sediments from the FH subjects, the mean contents (nmol glucose/mg protein per 24 hr) of GlcCer, GalCer, and LacCer were 2.7, 1.9, and 15.8 times higher, respectively, than in normals. The mean contents (μg/mg protein per 24 hr) of total cholesterol and phospholipid in the urinary sediment of FH (1.1 and 224, respectively) and normals (0.8 and 220) were similar. The mean contents of GlcCer, GalCer, and LacCer, expressed in terms of the cholesterol content of urinary sediment (nmol glucose/μg cholesterol per 24 hr), were increased 3.4-, 1.6-, and 5.4-fold, respectively, in the FH homozygotes. Of the five FH homozygotes, only one, who had undergone a portacaval shunt and was also receiving lipid-lowering therapy, had a normal value of LacCer. The other four FH homozygotes had levels of LacCer that were 3- to 55-fold higher (nmol glucose/mg protein per 24 hr) and 5.5- to 7.3-fold higher (nmol glucose/μg cholesterol per 24 hr) than the mean of the normals. One homozygote underwent plasma exchange therapy that reduced both the baseline urinary (nmol glucose/24 hr) and plasma (nmol/100 ml) LacCer levels from 86 to 7 and from 1491 to 852, respectively. Eleven days after plasma exchange, the urinary LacCer levels approached pre-exchange levels (59 nmol glucose/24 hr). The data indicate that there is an abnormality of GSL metabolism associated with familial hypercholesterolemia and that the urinary excretion of GSL can be modified by plasma exchange therapy.