Cara East

Combination drug therapy for familial combined hyperlipidemia.

STUDY OBJECTIVE To compare the efficacy of gemfibrozil and colestipol with gemfibrozil and lovastatin in patients with familial combined hyperlipidemia. DESIGN A prospective, randomized trial. SETTING An outpatient clinical research center in a tertiary care center. PATIENTS Seventeen patients with familial combined hyperlipidemia documented by studies of first-degree relatives; nine patients with type 2b hyperlipoproteinemia, and eight patients with type 4 hyperlipoproteinemia. INTERVENTIONS Baseline lipid, lipoprotein, and apolipoprotein levels were obtained during control periods on diet alone and on gemfibrozil therapy. Patients then received gemfibrozil and colestipol or gemfibrozil and lovastatin in a randomized order. MEASUREMENTS AND MAIN RESULTS In patients with type 2b hyperlipoproteinemia, gemfibrozil alone significantly reduced total cholesterol by 11%, and low density lipoprotein (LDL)-apolipoprotein B by 18%, did not change LDL-cholesterol, and raised high density lipoprotein (HDL)-cholesterol levels by 26%. Addition of either colestipol or lovastatin reduced LDL-cholesterol levels by 17% and 25%, respectively, compared to gemfibrozil alone. However, colestipol mitigated the HDL-cholesterol raising effect of gemfibrozil and did not further reduce LDL-apolipoprotein B levels. In contrast, addition of lovastatin caused an additional reduction of LDL-apolipoprotein B 19% compared with gemfibrozil alone. In patients with type 4 hyperlipoproteinemia, gemfibrozil alone reduced triglycerides by 40%, raised HDL-cholesterol by 26%, and increased LDL-cholesterol levels by 29%. The addition of either colestipol or lovastatin reduced LDL-cholesterol levels by 34% and 33%, respectively (compared with gemfibrozil alone), but greater reductions of LDL-apolipoprotein B (30% with lovastatin compared with 15% with colestipol, compared with gemfibrozil alone), and increases in HDL-cholesterol levels (8% increase with lovastatin compared with 10% decrease with colestipol, compared to gemfibrozil alone) were seen with the lovastatin combination. CONCLUSIONS Although gemfibrozil with either colestipol or lovastatin favorably altered lipoprotein levels in patients with hypertriglyceridemia and familial combined hyperlipidemia, the combination of gemfibrozil and lovastatin appeared superior overall.

Detection of Familial Hypercholesterolemia by Assaying Functional Low-Density-Lipoprotein Receptors on Lymphocytes

In familial hypercholesterolemia, structural and functional abnormalities of the receptor for low-density lipoprotein (LDL) lead to hypercholesterolemia and premature atherosclerosis. We have developed a simplified method to identify LDL-receptor defects in peripheral-blood lymphocytes. When lymphocytes are cultured in lipoprotein-depleted medium and endogenous sterol biosynthesis is suppressed with mevinolin, mitogen-stimulated proliferation of lymphocytes is dependent on an exogenous source of cholesterol. Whereas a small concentration of supplemental LDL cholesterol (3 to 4 micrograms per milliliter) permits a maximal response in normal lymphocytes, even high concentrations (10 to 50 micrograms per milliliter) are unable to support the proliferation of lymphocytes from patients with homozygous familial hypercholesterolemia. Thus, functional LDL receptors are necessary to allow lymphocyte proliferation in these cultures. The response of lymphocytes from patients with hyperlipidemia not caused by defective LDL receptors was like that of normal cells. In contrast, the response of lymphocytes from patients with heterozygous familial hypercholesterolemia was intermediate between that of homozygotes and that of normal or hyperlipidemic controls. Our method can therefore be used to identify persons who are heterozygous for abnormalities of LDL receptors.

Demonstration of 26-hydroxylation of C27-steroids in human skin fibroblasts, and a deficiency of this activity in cerebrotendinous xanthomatosis.

26-Hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol and other C27-steroids was demonstrated in cultured skin fibroblasts from healthy individuals. Activities in skin fibroblasts were approximately 5-10% of those previously found in human liver homogenates, and were inhibited by CO. The apparent Km was lowest for 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol (1.3 mumol/liter) and highest for 5-cholestene-3 beta, 7 alpha-diol (12 mumol/liter). The rate of 26-hydroxylation was highest with 7 alpha-hydroxy-4-cholesten-3-one. These characteristics are similar to those of hepatic mitochondrial C27-steroid 26-hydroxylase. In skin fibroblasts from three patients with cerebrotendinous xanthomatosis (CTX), 26-hydroxylation of C27-steroids proceeded at a rate of only 0.2-2.5% of healthy controls. No accumulation of endogenous 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol could be demonstrated in these cells, and the lowered formation of radioactive, 26-hydroxylated products could not be explained by dilution of the labeled exogenous substrate. The present results add strong evidence to the concept that the primary metabolic defect in CTX is a deficiency of C27-steroid 26-hydroxylase.

Preliminary report: Treatment of type 3 hyperlipoproteinemia with mevinolin

Type 3 hyperlipoproteinemia (HLP) results from the accumulation in plasma of remnants of very low density lipoproteins (VLDL) due to a defect in apolipoprotein E. Current data suggest that VLDL remnants can be removed by the same receptors that remove low density lipoproteins (LDL). Mevinolin has been shown to enhance clearance of LDL by LDL receptors. In this study, mevinolin markedly lowered both VLDL remnants and LDL in a patient with type 3 HLP, presumably by increasing the activity of LDL receptors.

Increased catabolism of VLDL-apolipoprotein B and synthesis of bile acids in a case of hypobetalipoproteinemia☆

A 29-year-old man is described who has reduced concentrations of low density lipoprotein (LDL)-cholesterol seemingly due to an unusual variant of hypobetalipoproteinemia. The patient developed retinitis pigmentosa at age 14. When studied at age 28, his total cholesterol was 104 mg/dL, triglycerides 58 mg/dL, LDL-cholesterol 44 mg/dL, and HDL-cholesterol 51 mg/dL. Lipid and lipoprotein levels of his parents and sister were normal. His excretion of bile acids (13.9 mg/kg/d) was markedly elevated at about three times normal, although absorption rates of cholesterol and bile acids appeared to be in the normal range. His high excretion of bile acids equates to a threefold increase in bile acid synthesis. Isotope kinetic studies of his lipoproteins produced unexpected findings. Total production of VLDL-apolipoprotein B (apo B) was estimated to be 20.8 mg/kg/d, which was in the normal range. Synthesis of VLDL-triglycerides was also normal at 12.0 mg/kg/h. However, 75% of VLDL-apo B was removed directly from the circulation, which was much higher than values for direct removal of VLDL-apo B in control subjects. His production rate of LDL-protein (5.2 mg/kg/d) consequently was below normal, although his fractional catabolic rate for LDL (0.40 pools/d) was not distinctly elevated. These data suggest that the patients hypobetalipoproteinemia was due to increased direct removal of VLDL remnants and not to reduced synthesis of VLDL-apo B; this abnormality may have been the result of enhanced activity of LDL receptors, which in turn was secondary to increased synthesis of bile acids.

Low-density lipoprotein metabolism in cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is a rare disorder characterized by a defect in conversion of cholesterol into bile acids, increased plasma levels of cholestanol, and accumulations of sterols in tendons, brain, and coronary arteries. Despite the presence of tendon xanthomas, patients with CTX frequently have low levels of plasma cholesterol and low density lipoproteins (LDL). The mechanisms for a low LDL are not understood. The present study, therefore, was carried out to examine the metabolism of LDL in a 58-year-old black man with CTX. This particular patient had an LDL-cholesterol in the mid-normal range (149 +/- 6 mg/dL). Nonetheless, his fractional catabolic rate (FCR) for LDL-apolipoprotein (apo-LDL) was 0.45 pools/d, which was increased compared to 15 aged-matched men (FCR, 0.30 +/- 0.01 pools/d). His production rate for apo-LDL (18.5 mg/kg-d) also was increased compared to those of middle-aged men (13.5 +/- 2.5 mg/kg-d). Since the underlying defect in CTX can be reversed by administration of chenodeoxycholic acid (chenodiol), the patient was treated with chenodiol (250 mg 4X daily), and measurements of LDL kinetics were repeated. During chenodiol therapy, his LDL-cholesterol concentration rose significantly to 165 +/- 12 mg/dL; his FCR for apo-LDL fell to 0.29 pools/d; and his production rate of apo-LDL declined to 14.4 mg/kg-d. We postulate that chenodiol suppressed the excessive synthesis of cholesterol and bile acids, which had two effects. It curtailed both the overproduction of LDL and the excessive synthesis of LDL receptors, the latter being responsible for the high FCR of apo-LDL in the untreated state.

Normalization of LDL receptor function by lymphocytes of patients with heterozygous familial hypercholesterolemia after treatment with plasma cholesterol lowering agents

Low density lipoprotein (LDL)-dependent growth of mitogen-activated lymphocytes, inhibited in their capacity to synthesize cholesterol endogenously, can be used as an assay of functional receptors for LDL. Using this technique, abnormalities can be detected in circulating lymphocytes obtained from patients with familial hypercholesterolemia (FH). Functional lymphocyte LDL receptor activity was decreased in patients with heterozygous FH. Following treatment with the specific inhibitor of cholesterol synthesis, lovastatin, alone or in combination with a bile acid-binding resin, there was increased expression of functional lymphocyte LDL receptors in five of nine patients. Plasma LDL cholesterol levels decreased in all nine patients. Three other patients who were only studied while receiving therapy also manifested increased expression of functional lymphocyte LDL receptors. The degree of improvement in plasma LDL cholesterol did not predict the effect on lymphocyte LDL receptor function. Longitudinal studies indicated that an increase in functional LDL receptor activity could be observed with 4 weeks of therapy and persisted for at least 18 months on continuous treatment. These results provide direct evidence that therapy with lovastatin and a bile acid-binding resin can lead to increased expression of functional LDL receptors by lymphocytes in the majority (eight of 12) of patients with heterozygous FH.

Reduced C27-steroid 26-hydroxylase activity in heterozygotes for cerebrotendinous xanthomatosis

C27-steroid 26-hydroxylase activity in fibroblasts from two heterozygotes for CTX was determined, using an optimized enzyme assay. With 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol, 5 beta-cholestane-3 alpha,7 alpha-diol, 7 alpha-hydroxy-4-cholestane-3-one or 7 alpha-hydroxycholesterol as substrates, the activities were about 50% of those of control cells. The Km for the substrates was not increased in the CTX heterozygotes. These findings support that deficiency of the C27-steroid 26-hydroxylase is the primary enzymatic defect in CTX.