Liver Transplantation to Provide Low-Density-Lipoprotein Receptors and Lower Plasma Cholesterol in a Child with Homozygous Familial Hypercholesterolemia

Abstract

A six-year-old girl with severe hypercholesterolemia and atherosclerosis had two defective genes at the low-density-lipoprotein (LDL) receptor locus, as determined by biochemical studies of cultured fibroblasts. One gene, inherited from the mother, produced no LDL receptors; the other gene, inherited from the father, produced a receptor precursor that was not transported to the cell surface and was unable to bind LDL. The patient degraded intravenously administered 125 I-LDL at an extremely low rate, indicating that her high plasma LDL-cholesterol level was caused by defective receptor-mediated removal of LDL from plasma. After transplantation of a liver and a heart from a normal donor, the patient's plasma LDL-cholesterol level declined by 81 per cent, from 988 to 184 mg per deciliter. The fractional catabolic rate for intravenously administered 125 I-LDL, a measure of functional LDL receptors in vivo, increased by 2.5-fold. Thus, the transplanted liver, with its normal complement of LDL receptors, was able to remove LDL cholesterol from plasma at a nearly normal rate.We conclude that a genetically determined deficiency of LDL receptors can be largely reversed by liver transplantation. These data underscore the importance of hepatic LDL receptors in controlling the plasma level of LDL cholesterol in human beings.Familial hypercholesterolemia is caused by mutations in the gene encoding the low-densitylipoprotein (LDL) receptor. This cell-surface receptor normally removes cholesterol-carrying LDL from the circulation. 1 Persons with two mutant LDL-receptor genes (homozygous familial hypercholesterolemia) produce few or no LDL receptors and therefore remove LDL from plasma at a reduced rate. As a result, LDL accumulates in plasma to levels up to eight times normal, and total plasma cholesterol levels frequently reach 1000 mg per deciliter (30 mmol per liter). These patients almost always have severe atherosclerosis in childhood, with death from myocardial infarction often occurring before the age of 20. 2 The heterozygous form of familial hypercholesterolemia, in which a single mutant LDLreceptor gene is inherited, occurs at a frequency of 1 in 500 in the general population. Affected persons produce on average about half the normal number of LDL receptors. 2 LDL accumulates to twice the normal level, and symptomatic atherosclerosis usually occurs in the fourth and NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript fifth decades of life. Typically, each heterozygote for familial hypercholesterolemia will transmit the mutant gene to half of his or her children, who then become heterozygotes. When two heterozygotes marry (as occurs in 1 of 250,000 marriages), one fourth of the offspring will inherit a copy of the mutant LDL-receptor gene from both parents, and these offspring will be homozygotes.Considerable progress has been made in the understanding of familial hypercholesterolemia at the basic and clinical levels. The LDL receptor has been purified, and specific antibodies have been...

Cell migration and chimerism after whole-organ transplantation: The basis of graft acceptance

“…For example, the decline in cholesterol levels after liver transplantation in patients with familial hypercholesterolemia (66) was ascribed to the new supply of low-density lipoprotein receptors of the allograft hepatocytes (67) . It seems likely now that the amelioration of this disorder by liver transplantation is explained in part by low-density lipoprotein receptors of widely disseminated donor cells that are not hepatocytes.…”

LDL-cholesterol lowering and atherosclerosis - clinical benefit and possible mechanisms: an update

“…In addition to drug treatment, alternative ap proaches to cholesterol-lowering have been per formed by portocaval shunting, liver transplantation and plasmapheresis [61][62][63]. The latter has been shown to reduce mortality of CAD [64].…”

A sensitive noninvasive method for monitoring successful liver-directed gene transfer of the low-density lipoprotein receptor in Watanabe hyperlipidemic rabbits in vivo

“…8 Liver is the clinically most important site of the LDLR expression, since liver transplantation is able to cure FH. 9 Owing to these features, FH was among the first diseases for the development of liver-directed clinical gene therapy strategies. Two established animal models are available, LDLR knockout mice 10 and Watanabe hypercholesterolemic (WHHL) rabbits.…”