Familial Hypercholesterolemia Heterozygotes Research Articles

Effects of lovastatin alone and in combination with cholestyramine on serum lipids and apolipoproteins in heterozygotes for familial hypercholesterolemia

We have studied the effect of lovastatin, an inhibitor of the rate-limiting enzyme in cholesterol biosynthesis (3-hydroxy-3-methylglutaryl coenzyme A reductase), alone and in combination with the bile acid sequestrant cholestyramine on lipid parameters in 30 heterozygous patients with familial hypercholesterolemia (FH) during a 20-week open trial. Lovastatin 40 mg bid (twice daily) decreased significantly total serum cholesterol, low density lipoprotein (LDL)-cholesterol, triglycerides and apolipoprotein B by 36%, 45%, 29% and 11%, respectively, while high density lipoprotein (HDL)-cholesterol and apolipoprotein A-I were increased significantly by 16% and 37%, respectively. These data are consistent with a reduction in both the number of LDL particles and in their cholesterol content. Addition of cholestyramine 4 g bid caused a significant further decrease in total serum cholesterol and LDL-cholesterol to a total of 43% and 61%, respectively. The addition of 4 g bid or 8 g bid of cholestyramine caused only minor changes in the other lipid parameters. No effect was found by these drugs on Lp(a) lipoprotein level. We conclude that lovastatin alone or in combination with a small dose of cholestyramine normalizes the lipid profile in most FH heterozygotes.

Effects of CS-514 (eptastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on serum lipid and apolipoprotein levels in heterozygous familial hypercholesterolemic patients treated by low density lipoprotein (LDL)-apheresis.

Nine heterozygous patients with familial hypercholesterolemia (FH) were treated by low density lipoprotein (LDL)-apheresis using dextran sulfate cellulose columns. After more than 3 procedures of LDL-apheresis without drug therapy, combination therapy with LDL-apheresis and CS-514 (eptastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase, at a dose of 10 mg twice daily was started. Pre- and post-apheresis serum cholesterol levels were decreased significantly by CS-514, from 289 +/- 24 mg/dl (mean +/- SEM) to 247 +/- 25 mg/dl and from 118 +/- 7 mg/dl to 106 +/- 9 mg/dl, respectively. Pre- and post-apheresis apolipoprotein B levels decreased significantly on CS-514 from 160 +/- 9 mg/dl to 138 +/- 8 mg/dl and from 58 +/- 6 mg/dl to 45 +/- 6 mg/dl, respectively. No adverse effects were observed during the combination therapy. Thus, the addition of an inhibitor of HMG-CoA reductase to LDL-apheresis is a useful method for further reducing serum cholesterol and apolipoprotein B levels in FH heterozygotes.

Enzyme-linked immunosorbent assay for apolipoprotein B on dried blood spot derived from newborn infant: its application to neonatal mass screening for hypercholesterolemia.

Hypercholesterolemia is a risk factor for atherosclerotic cardiovascular disease, and early diagnosis and treatment should be given attention. We developed a simple and sensitive enzyme-linked immunosorbent assay (ELISA) for apolipoprotein B (apoB) on a dried blood spot (DBS). The specificity of this assay was investigated by constructing curves for other proteins. The cross-reactivity was negligible. The mean intra- and intercoefficients of variation were 5.2 and 7.8%, respectively. We used phosphate buffer with Triton X-100 for extracting apoB on DBS. The elution of apoB was stable up to 30 days after bleeding. The correlation between plasma and DBS apoB was r = 0.94, p less than 0.005, n = 55. Using this method, we screened 2,500 babies between 5 and 7 days of age. The mean +/- SD of DBS apoB was 75 +/- 15 U. Seven hypercholesterolemic neonates were detected. Family studies of these neonates disclosed one definite and two suspected heterozygotes for familial hypercholesterolemia. Four other neonates showed no related familial background. This ELISA method for assaying apoB should prove to be a useful tool for large mass screening for hypercholesterolemia, particularly in the newborn.

Enzyme‐Linked Immunosorbent Assay for Apolipoprotein B on Dried Blood Spot Derived from Newborn Infant

Summary:Hypercholesterolemia is a risk factor for atherosclerotic cardiovascular disease, and early diagnosis and treatment should be given attention. We developed a simple and sensitive enzyme‐linked immunosorbent assay (ELISA) for apolipoprotein B (apoB) on a dried blood spot (DBS). The specificity of this assay was investigated by constructing curves for other proteins. The crossreactivity was negligible. The mean intra‐ and intercoefficients of variation were 5.2 and 7.8%, respectively. We used phosphate buffer with Triton X‐100 for extracting apoB on DBS. The elution of apoB was stable up to 30 days after bleeding. The correlation between plasma and DBS apoB was r = 0.94, p < 0.005, n = 55.Using this method, we screened 2,500 babies between 5 and 7 days of age. The mean ± SD of DBS apoB was 75 ± 15 U. Seven hypercholesterolemic neonates were detected. Family studies of these neonates disclosed one definite and two suspected heterozygotes for familial hypercholesterolemia. Four other neonates showed no related familial background. This ELISA method for assaying apoB should prove to be a useful tool for large mass screening for hypercholesterolemia, particularly in the newborn.

Plasma triglycerides related decrease in high-density lipoprotein cholesterol and its association with myocardial infarction in heterozygous familial hypercholesterolemia

Recent studies suggest that decreased levels of high-density liopoprotein (HDL) may contribute to the risk of premature occlusive atherosclerosis in familial hypercholesterolemia (FH). To investigate further, we have analyzed the concentration as well as distribution of HDL cholesterol in relation to plasma triglycerides and their influence on ischaemic heart disease in FH subjects. The study was carried out in 71 men with heterozygous FH and 46 matched controls. FH subjects were relatively young with a mean age of 38 ± 11 years. Tendon xanthomatas were observed in 57% of the subjects, whereas ischemic heart disease was identified in 33%. Compared to normals, the mean value of HDL cholesterol is significantly reduced by 21% in FH heterozygotes (42 ± 12 v 33 ± 9 mg/dL, P < 0.001). The decrease in HDL cholesterol is highly correlated to the levels of plasma triglycerides ( r = −0.50, P < 0.001) and VLDL cholesterol ( r = −0.53, P < 0.001). Moreover, HDL cholesterol decrease is not associated with elevated levels of LDL cholesterol ( r = −0.20, NS), which is the primary characteristic feature of FH subjects. However, HDL cholesterol decrease is weakly related to total plasma cholesterol concentration ( r = −0.24, P < 0.05). The body weight is also contributory to the reduction of HDL cholesterol ( r = −0.42, P < 0.01), probably due to its strong positive correlation to plasma triglycerides ( r = +0.54, P < 0.001). Grouping of subjects on the basis of triglyceride levels of less than 200 mg/dL (IIa phenotype) and more than 200 mg/dL (IIb phenotype) shows that the concentration of HDL cholesterol undergoes a further significant decrease in the latter group (36 ± 9 v 30 ± 11 mg/dL, P < 0.001). Since the level of LDL cholesterol is similar in both groups (314 ± 68 v 316 ± 76 mg/dL, NS), a further reduction in HDL cholesterol concentration results in an increased LDL/HDL ratio in IIb phenotypes. Although HDL cholesterol is normally distributed in controls and type IIa phenotypes, its distribution is skewed to lower values in type IIb. In addition to similar levels of LDL cholesterol, the presence of tendon xanthomatas is equally observed in both type IIa and type IIb subjects (51.1% and 62.5%, respectively). Similarly, the incidence of angina pectoris (19.2% and 12.5% in type IIa and type IIb, respectively) is also approximately the same in both groups. However, the differences are striking in the incidence of myocardial infarction (MI), which is increased three-fold (25% v 8.5%) in type IIb subjects, as compared to type IIa. These findings indicate that in addition to LDL excess, HDL deficiency associated with elevated plasma triglycerides contributes to the severity of ischemic heart disease, as revealed from the manifestation of MI in some FH heterozygotes.

家族性高コレステロール血症患者のLDLレセプター活性とそれに対する薬物療法の影響

We examined low density lipoprotein (LDL) receptor activities of 13 heterozygous patients with familial hypercholesterolemia (FH) using peripheral lymphocytes.The receptor activities were measured as the degradation of 125I-labeled LDL in lymphocytes which had been cultured for three days in 10% lipoprotein-deficient serum. After incubation, 10μg/ml of 125I-LDL were added to the medium in the presence or absence of 250μg/ml of nonlabeled LDL and then the lymphocytes were incubated for five hours further. The radioactivity of the trichloroacetic acid-soluble fraction of the medium was measured.As a result, LDL receptor activities of FH heterozygotes were revealed to correlate significantly and negatively with serum LDL-cholesterol concentration. If we combined them with those of two FH homozygotes and 18 hyperlipidemic patients other than FH and normolipidemic persons, the latter of which we reported previously (J. Jpn. Atheroscler. Soc. 12: 303-308, 1984), not only the grade of the negative correlation between LDL receptor activities and LDL-cholesterol became greater, but LDL receptor activities also correlated negatively with total cholesterol (TC) (p<0.01). Extrapolation from these data suggested that LDL receptor activity would disappear when TC concentration was higher than 718mg/dl. The value estimated agreed well with the clinical findings of FH.Then, probucol (750mg a day) was administered to eight heterozygous patients with FH for four to six months, by which TC concentration decreased significantly from 319.6±36.7 (mg/dl) to 282.3±17.4 (mg/dl). The result suggests that probucol is effective in the treatment of FH. The levels of LDL receptor activities in the pretreatment state was not correlated to the effectiveness of probucol treatment in each case.LDL receptor activities were also measured after probucol administration and were compared with those of the pretreatment state. There were a great variations of change of LDL receptor activity among the eight patients, and no definite trend of the activity could be found. But, it was suggested that the percentage change of TC concentration was correlated negatively with the difference in LDL receptor activity before and after probucol administration, that is, the more the TC concentration decreased, the more the LDL receptor activity increased.These results may suggest that the main action of probucol is not on LDL receptor and probucol indirectly influences LDL receptor activity by the change in serum cholesterol concentration.

Effects of fenofibrate on high and low density lipoprotein metabolism in heterozygous familial hypercholesterolemia

This study investigates the influence of pharmacological doses of fenofibrate on HDL and LDL metabolism in 5 familial hypercholesterolemia heterozygotes. Fenofibrate lowered plasma low density lipoprotein cholesterol (20%, P < 0.025), triglycerides (37%: P < 0.005) and apolipoprotein B (14%: P < 0.05) but increased apo A-I (20%; P = 0.01). Kinetic studies showed that the drug markedly increased the fractional catabolic rate of LDL-apo B by 59% and its synthetic rate by 36%. Fractional catabolic rate of apo A-I was also increased by 26% but accompanied by a much greater increase of its synthetic rate (49%). Thus the change in balance between catabolism and synthesis of both apoproteins affected by fenofibrate accounts for the observed plasma concentration changes, which may be considered as favourable with regard to the management of atherosclerosis.

Low density lipoprotein receptors in cultured skin fibroblasts from psoriasis patients.

Low density lipoprotein (LDL) receptor activity, measured as 125I-LDL association and degradation at 37 degrees C, was determined in cultured fibroblasts from involved as well as uninvolved skin obtained from 20 psoriasis patients. The same analyses were conducted in fibroblasts from two reference groups consisting of 19 heterozygotes for familial hypercholesterolemia and 16 normal subjects, respectively. Psoriasis patients had significantly lower LDL receptor activity than normals, and it was comparable to that of the heterozygotes for familial hypercholesterolemia. The reduced LDL receptor activity was not accompanied by an increase in total serum cholesterol. The psoriasis patients had a significant reduction in apo-B concentration, but did not differ from the normals in the other serum lipid or lipoprotein parameters. There was no difference in LDL receptor activity between involved and uninvolved skin from psoriasis patients. These results suggest that there is an abnormal cell membrane in dermal fibroblasts from psoriasis patients. Since their total serum cholesterol is normal, their low LDL receptor activity may be confined to dermal cells, leaving the hepatic lipid metabolism normal. The pathogenetic significance of this finding is unknown.

Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes.

In subject with heterozygous familial hypercholesterolemia (FH), a 50% deficiency of receptors for plasma low density lipoprotein (LDL) impairs the removal of LDL from plasma and produces hypercholesterolemia. In these patients mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, blocks cholesterol synthesis and lowers plasma LDL levels. To determine the mechanism for the LDL-lowering effect, we administered 131I-labeled LDL intravenously to six FH heterozygotes before and during treatment with mevinolin and calculated the apparent fractional catabolic rate (FCR) and synthetic rate for LDL. After mevinolin treatment, the mean plasma LDL-cholesterol level declined from 262 to 191 mg/dl (27% decrease), the mean FCR for 131I-labeled LDL increased from 0.30 to 0.41 pools per day (37% increase), and the mean calculated synthetic rate for LDL-protein did not change significantly. In one of FH heterozygote with an ileal bypass and in another who received colestipol, the addition of mevinolin caused, respectively, a 41% and 60% decrease in plasma LDL levels and a 60% and 100% increase in the FCR for plasma LDL. The contribution of receptor-dependent pathways to the FCR for plasma LDL was estimated in three FH heterozygotes by simultaneous measurements of the FCR for native 131I-labeled LDL and 125I-labeled glucosylated LDL, which does not bind to LDL receptors. Whereas the removal rate for native LDL increased after mevinolin treatment, the removal rate for glucosylated LDL did not change. The current data suggest that mevinolin alone or mevinolin plus bile acid depletion (i.e., ileal bypass or colestipol therapy) decreases plasma LDL levels primarily by raising the number of LDL receptors and, thus, enhancing the removal of LDL from plasma.

The metabolic basis of familial hypercholesterolemia.

Familial hypercholesterolaemia (FH) is a dominantly inherited error of metabolism characterised by a raised plasma low-density lipoprotein (LDL) concentration, xanthomas of skin and tendons, and a tendency to premature heart disease due to atherosclerosis of the coronary arteries. The clinical and biochemical abnormalities are more marked in homozygotes than in heterozygotes. Other biochemical changes include an increased concentration of very-low-density lipoprotein (VLDL) remnants and of a minor subfraction of high-density lipoproteins. Measurement of plasma lipoprotein turnover shows reduced fractional rates of catabolism of LDL and VLDL remnants, and increased production of LDL. Similar abnormalities are found in Watanabe rabbits, an inbred strain carrying a mutation similar to that responsible for FH. Cultured cells from human and animal tissues express surface receptors with high binding affinity for LDL. Binding of LDL to LDL receptors is followed by endocytosis and lysosomal digestion of the lipoprotein. Cultured cells from FH heterozygotes express only half the normal number of LDL receptors; those from homozygotes have little or no receptor activity and are therefore unable to degrade significant amounts of LDL by the LDL-receptor pathway. The LDL receptor has been isolated from cell membranes; it has a molecular weight of about 160 kd. Several different mutant forms of the receptor have been identified in the cells of FH homozygotes. The LDL-receptor pathway for the catabolism of LDL accounts for at least 1/3 of the total LDL catabolised by normal human subjects in vivo and almost none of that catabolised by FH homozygotes. Deficiency of LDL receptors accounts for the increased plasma concentrations of LDL and VLDL remnants in FH. The increased plasma concentration in these lipoproteins is the cause of deposition of lipid in xanthomas and arterial wall, but the mechanism by which lipoprotein enters the cells in which lipid accumulates is not yet understood.

The metabolism of very low density and intermediate density lipoproteins in patients with familial hypercholesterolaemia

The metabolism of apolipoprotein B (apoB) in very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) was studied in normal subjects and in patients with familial hypercholesterolaemia (FH) after an intravenous injection of autologous VLDL labelled with 125I. There were no significant differences in half life, pool size and turnover rate (mg/kg/h) of VLDL-apoB between the normal subjects, the FH heterozygotes and the FH homozygotes. IDL-apoB metabolism in the FH patients differed significantly from that in the normal subjects. In the FH patients, the rise to the maximum of the specific activity curve was slower, the half life of the descending limb of the specific-activity curve was longer, the fractional rate of turnover was lower and the plasma concentration was higher than in the normals. The effect of cholestyramine on IDL-apoB metabolism in the normal subjects did not differ from that in the FH heterozygotes and homozygotes, though cholestyramine is known to stimulate hepatic uptake of low density lipoprotein (LDL) by the LDL receptor. It is suggested that in normal human subjects the LDL receptor makes some contribution to the hepatic uptake of IDL-apoB derived from VLDL, but that IDL uptake is mediated partly by a separate receptor that recognizes apolipoprotein E but not apoB.

LDL receptor studies in children with heterozygous familial hypercholesterolemia (FH): measurement of sterol synthesis in blood lymphocytes.

Sterol synthesis was measured in lymphocytes from 48 members of 10 families with familial hypercholesterolemia (FH) under three sets of conditions. First the synthesis of LDL receptors and sterols were maximally stimulated by incubation of lymphocytes in lipoprotein-deficient serum. Secondly sterol synthesis was suppressed by the addition of LDL and thirdly sterol synthesis was maximally suppressed by the addition of 7-ketocholesterol. In five of the ten families LDL suppression of sterol synthesis in FH heterozygotes was only about half of the LDL suppression in normals. In four families, however, there was a considerable overlapping of LDL suppression in FH heterozygotes and normals. Finally in one family LDL suppression was strictly normal in FH heterozygotes who thus appear to have a different type of FH not involving an impaired LDL receptor function.

The fatty acid composition of serum low density lipoprotein- and lymphocyte cholesterol esters in children with heterozygous familial hypercholesterolemia.

The content of free and esterified cholesterol in serum low density lipoprotein (LDL) was measured in 19 children with heterozygous familial hypercholesterolemia (FH) and in 10 normal siblings. In FH both free and esterified cholesterol were found to be elevated. Furthermore the fatty acid composition of serum LDL- and lymphocyte cholesterol esters was determined. However, no difference was found between FH heterozygotes and normals thus indicating that LDL-hypocatabolism typically found in FH does not correlate with an abnormal fatty acid composition of LDL-cholesterol esters nor with an impaired cholesterol esterification intracellularly in lymphocytes.

Metabolic Studies in Familial Hypercholesterolemia

To investigate the gene-dosage effect in familial hypercholesterolemia (FH), metabolic studies were conducted in a group of well-characterized patients with either heterozygous (n = 7) or homozygous (n = 7) FH and the results were compared to those obtained in normal subjects (n = 6). The turnover of (125)I-labeled low-density lipoprotein (LDL) was measured in all of the normals, all but one of the FH heterozygotes, and in all of the homozygotes. Chemical cholesterol balance was performed simultaneously with the (125)I-LDL turnover in all seven of the homozygotes. With regard to (125)I-LDL turnover, FH homozygotes, who possess two doses of the mutant FH gene, exhibited a threefold increase in the rate of apoLDL synthesis while the fractional catabolic rate (FCR) for the apoprotein was only about one-third of normal. Heterozygotes, who have only one dose of the mutant FH gene, exhibited intermediate values for both parameters; that is, the FCR was two-thirds of normal and the apoLDL synthetic rate was 1.7-fold greater than normal. THE DATA INDICATE THAT THE SINGLE GENE DEFECT IN FH PRODUCES TWO DISTINCT ABNORMALITIES OF LDL METABOLISM: (a) an increase in the synthetic rate for apoLDL and (b) a decrease in the efficiency of apoLDL catabolism. Both defects are more severe in FH homozygotes than in heterozygotes. The FCR for apoLDL in the homozygotes appeared to be fixed at congruent with 17%/d whereas the plasma LDL level varied about twofold. These findings suggest that the twofold variation in plasma LDL levels observed in these seven patients is caused by variation in the plasma apoLDL synthetic rates. Consistent with this conclusion was the finding that the correlation between the plasma LDL level and the apoLDL synthetic rates in the seven FH homozygotes was 0.943. The rate of total body cholesterol synthesis determined by chemical cholesterol balance did not appear to clearly differ between normals and patients with either one or two mutant FH genes. Two of the youngest FH homozygotes exhibited cholesterol overproduction but the other five did not. No consistent abnormality of bile acid metabolism was observed in these patients. Because the daily plasma flux of cholesterol on LDL is about threefold greater than the amount of cholesterol produced per day, a significant amount of the cholesterol liberated from LDL degradation must be reused.

Genetics of the low density lipoprotein receptor. Diminished receptor activity in lymphocytes from heterozygotes with familial hypercholesterolemia.

Using circulating mononuclear cells as a readily available tissue and using the rate of high affinity degradation of 125-I-labeled low density lipoprotein (LDL) as an index of cell surface LDL receptor activity, we have measured receptor activity in cells from 53 individuals. This group includes 32 healthy subjects, 15 subjects with the heterozygous form of familial hypercholesterolemia, and 6 subjects with hyperlipidemic disorders other than familial hypercholesterolemia. 7 of the healthy subjects and 10 of the heterozygotes were members of a single large kindred with five-generation transmission of the mutant familial hypercholesterolemia gene. LDL receptor activity was assayed in blood mononuclear cells under two sets of conditions. First, 125I-LDL degradation was measured in purified lymphocytes that had been incubated for 3 days in the absence of lipoproteins so as to induce a high level of LDL receptor activity. Phase-contrast autoradiograms of cells incubated with 125I-LDL and electron micrographs of cells incubated with ferritin-labeled LDL confirmed the existence of LDL receptors on lymphocytes. Second, 125I-LDL degradation was measured in mixed mononuclear cells (85-90% lymphocytes and 5-15% monocytes) immediately after their isolation from the bloodstream. This assay represented an attempt to assess the number of receptors actually expressed on the cells when they were in the circulation. Under both sets of conditions, cells from the familial hypercholesterolemia heterozygotes expressed an average of about one-half the normal number of LDL receptors. The current findings are consistent with the conclusion that heterozygotes with familial hypercholesterolemia possess only one functional allele at the LDL receptor locus and that the consequent deficiency of LDL receptors produces the clinical syndrome of heterozygous familial hypercholesterolemia.

Heterozygous familial hypercholesterolemia: Failure of normal allele to compensate for mutant allele at a regulated genetic locus

In normal human fibroblasts, the synthesis of a cell surface receptor for plasma low density lipoprotein (LDL) is regulated by a sensitive system of feedback suppression. The number of functional LDL receptors declines by more than 20 fold when cellular stores of esterified cholesterol are increased by incubation of cells with an exogenous source of cholesterol. Fibroblasts from patients with the heterozygous form of familial hypercholesterolemia (FH) possess one functional allele and one nonfunctional allele at the LDL receptor locus. In the current studies, we have examined the effect that this deficiency produces upon the pattern of regulation of the single functional allele at the LDL receptor locus. Under growth conditions that induced a maximal rate of LDL receptor synthesis (that is, growth in the absence of an exogenous source of cholesterol), the FH heterozygote cells produced about one half as many functional LDL receptors as did the normal cells. More importantly, when grown in the presence of increasing amounts of exogenous cholesterol, the FH heterozygote and normal cells suppressed their respective LDL receptor activities in parallel. Over a wide range of LDL receptor activities, at each level of cellular esterified cholesterol, the FH heterozygote cells expressed about one half as many receptors as did the normal cells. These data indicate that in the FH heterozygote cells, the receptor regulatory mechanism dictates that the normal allele produce only the amount of gene product that it would normally produce at a given level of cellular esterified cholesterol. The failure of the regulatory mechanism to stimulate the normal allele at the LDL receptor locus to produce twice its normal amount of gene product leaves the FH heterozygote cells with a persistent 50% deficiency in LDL receptors under all conditions of cell growth.

Reduction in cholesterol and low density lipoprotein synthesis after portacaval shunt surgery in a patient with homozygous familial hypercholesterolemia.

The turnover of 125I-labeled low density lipoprotein (LDL) and the total body balance of cholestrol were studied in a 6-yr-old girl with the homozygous form of familial hypercholesterolemia (FH) before and after the surgical creation of an end-to-side portacaval shunt. The results were compared with those of similar studies simultaneously performed in untreated patients with the heterozygous form of FH and with the results of earlier studies performed on normolipidemic subjects. Before shunt surgery, the rate of synthesis of LDL in the FH homozygote (mg/kg per day) was fourfold higher than in normolipidemic subjects and twofold higher than in her heterozygous mother. The fractional catabolic rate for LDL in the homozygote was decreased to 33% of normal control values. The rate of cholesterol synthesis, estimated by chemical sterol balance, was higher in the FH homozygote than in two FH heterozygotes of similar age studied simultaneously. When considered in relation to the markedly elevated level of plasma cholesterol, the observed rate of cholesterol synthesis in the FH homozygote was inappropriately elevated. Bile acid production was normal in all three children. 5 mo after shunt surgery, the rate of LDL synthesis in the homozygote had declined by 48% as compared with the preoperative value, and this caused a 39% drop in the plasma LDL cholesterol level despite a 17% reduction in the fractional catabolic rate of the lipoprotein. The rate of cholesterol synthesis fell by 62% as compared with the preoperative value. The findings of an inappropriately elevated rate of production of both cholesterol and LDL as well as a reduced fractional catabolic rate for the lipoprotein in the untreated FH homozygote are consistent with results of studies in cultured fibroblasts indicating that the primary genetic defect in FH involves a deficiency in a cell-surface receptor for LDL that regulates both cholesterol synthesis and LDL degradation. Although the mechanism for the decline in production of cholesterol and LDL after portacaval shunt surgery is unknown, it was observed that these changes were associated with marked increases in the plasma concentrations of bile acids and glucagon.