Homozygous familial hypercholesterolemia. A possible biochemical explanation of clinical heterogeneity

Patients with homozygous familial hypercholesterolemia fall into two groups: one responds to diet and drug therapy; the other does not. Fibroblasts from patients in each group were compared for low-density lipoprotein suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and low-density lipoprotein binding. In fibroblasts from four therapy-responsive patients, low-density lipoprotein (100 mug per milliliter) suppressed 3-hydroxy-3-methylglutaryl coenzyme A reductase activity to 41 +/- 12 per cent of control (without low-density lipoprotein) whereas fibroblast enzyme activity from two therapy-unresponsive patients was not suppressed (P less than 0.001). Low-density lipoprotein binding to fibroblasts from both groups was defective as compared to normal controls. Fibroblasts from two therapy-responsive patients had specific binding of low-density lipoprotein of 27 +/- 4 per cent of normal -- greater than the 12 +/- 2 per cent (P less than 0.005) binding to fibroblasts from one therapy-unresponsive patient. These biochemical differences may help explain the variable response to therapy in homozygous familial hypercholesterolemia.