Paul Samuel

Heterogeneity of cholesterol homeostasis in man. Response to changes in dietary fat quality and cholesterol quantity.

Studies were carried out to examine the effects of dietary fat and cholesterol on cholesterol homeostasis in man. 75 12-wk studies were carried out during intake of 35% of calories as either saturated or polyunsaturated fat, first low and then high in dietary cholesterol. Dietary fat and cholesterol intakes, plasma lipid and lipoprotein levels, cholesterol absorption and sterol synthesis in isolated blood mononuclear leukocytes were measured during each diet period. In 69% of the studies the subjects compensated for the increased cholesterol intake by decreasing cholesterol fractional absorption and/or endogenous cholesterol synthesis. When an increase in plasma cholesterol levels was observed there was a failure to suppress endogenous cholesterol synthesis. Plasma cholesterol levels were more sensitive to dietary fat quality than to cholesterol quantity. The results demonstrate that the responses to dietary cholesterol and fat are highly individualized and that most individuals have effective feedback control mechanisms.

Absorption of bile acids from the large bowel in man

The absorption of bile acids from the human large bowel was studied in eight patients. All patients had cholecystitis and cholelithiasis and had to undergo cholecystectomy. Cholic acid-(14)C was injected during surgery into the lumen of the cecum, hepatic flexure of the colon, or transverse colon in six patients, under the visual control of the surgeon. Common duct bile was collected by T tube daily for 5 days, and bile acids were extracted. Significant amounts of radioactivity appeared in T tube bile in each patient. T tube bile acids contained a total of 43.6-84.6% of the administered radioactivity; the average for the six patients was 58.9%. The majority of the tracer was excreted during the first 24 hr. In an additional patient cholic acid-(14)C was given in the form of an enema 5 days postoperatively. In this subject 30.8% of the retained radioactivity was excreted through the T-tube in 48 hr. The labeled cholic acid was recovered as both cholic and deoxycholic acid from T tube bile. Thin-layer chromatographic analysis of the bile acid samples indicated that the fraction of radioactivity recovered as deoxycholate increased with time during the postoperative period. Gas-liquid chromatographic analysis showed that the daily total quantity of excreted bile acids increased significantly from the 1st-5th days of the experiment. The amount of cholate excreted in T tube bile increased markedly with time, that of chenodeoxycholate increased moderately, and that of deoxycholate decreased sharply during the 5 days of the experiment. In three patients, injection of radiopaque material mixed with the tracer showed no evidence of regurgitation into the small bowel by serial X-rays. In an additional patient, tube aspirate from the terminal ileum contained no radioactivity. The results indicate that cholic acid is converted to deoxycholic acid in the human colon, and both of these bile acids are absorbed from the human large bowel in significant amounts. These data establish the previously unproved concept that significant absorption of bile acids takes place from the large bowel of man.

Effects of neomycin on absorption, synthesis, and/or flux of cholesterol in man.

The mode of action of the hypocholesteremic drug neomycin (2 g/day) was studied in four patients. All showed a significant reduction in plasma cholesterol concentrations (mean 25 percent, range 18-31 percent), and in one of three patients with hyperglyceridemia there was a decrease of plasma triglycerides of 26 percent. Cholesterol absorption was measured in three of four patients: there was a marked decrease. Sterol balance studies in four patients showed an unabating increase in fecal neutral steroid excretion (mean increase 345 mg/day, range 323-361) for 3-5 wk after plasma cholesterol levels had reached a new and lower plateau. Fecal acidic steroid excretion increased temporarily in two patients, with a sustained increase of 93 mg/day in only one. Daily stool weights increased significantly in three of four patients, though none had steatorrhea; there was a significant reduction in excretion of secondary bile acids; neutral sterol degradation rates were not affected by the drug. Slopes of plasma cholesterol-specific activity time curves did not change. These results fail to support the suggestion that neomycin acts as a bile acid precipitant. The finding of increased fecal neutral steroid excretion is consistent with decreased cholesterol absorption, but also with increased cholesterol absorption, but also with increased cholesterol synthesis (secondary to release of negative feedback control), with increased flux of cholesterol from tissues, or with a combination of all three actions.

Effects of fenofibrate on plasma lipids. Double-blind, multicenter study in patients with type IIA or IIB hyperlipidemia.

Of 240 patients with Type IIa and IIb hypercholesterolemia recruited in 11 centers, 227 were randomized to double-blind treatment with either fenofibrate (100 mg three times daily) or matching placebo for 24 weeks. A group of 192 of these patients were studied for a further 24 weeks during which all received fenofibrate in open label fashion. For the 92 Type IIa patients receiving fenofibrate in the double-blind phase, there were significant reductions (p less than 0.01 compared to baseline) in total plasma cholesterol (-18%), LDL-cholesterol (-20%), VLDL-cholesterol (-38%) and total triglycerides (-38%). Mean plasma HDL-cholesterol in these patients increased by 11% (p less than 0.01). With the exception of LDL, which was not high before treatment, similar changes were seen in the 24 fenofibrate-treated Type IIb subjects. Lipid parameters of placebo-treated patients did not change significantly. This pattern of change was repeated in the open period for the 94 patients previously on placebo, while the 98 who had been on fenofibrate remained stable with small further reductions in total and LDL cholesterol (-38% and -5.5% respectively). Adverse effects were some allergic-type skin reactions early in treatment and an occasional increase in transaminases, BUN, or creatinine. The results were similar to those obtained in European open trials of fenofibrate and were better than the lipid changes seen at comparable times in the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) cholestyramine study.

Effects of fenofibrate on plasma lipoproteins in hypercholesterolemia and combined hyperlipidemia

To investigate the lipoprotein effect of fenofibrate in hypercholesterolemia or combined hyperlipidemia (types II A and II B hyperlipidemias, respectively), 240 patients were recruited and 227 randomized to a double-blind randomized trial lasting 24 weeks and 192 patients continued to participate in an open-label phase for another 24 weeks. A 100-mg dose of fenofibrate or a matching placebo was given three times daily. Fenofibrate side effects in excess of placebo affected 6 percent of fenofibrate users and were confined almost entirely to skin rashes. In 180 hypercholesterolemic patients randomly assigned to receive fenofibrate versus placebo, triglyceride and very low-density lipoprotein cholesterol levels decreased 38 percent, total cholesterol levels decreased 17.5 percent, and low-density lipoprotein cholesterol levels decreased 20.3 percent with fenofibrate treatment. High-density lipoprotein cholesterol levels increased 11.1 percent with a decrease in the low-density lipoprotein cholesterol: high-density lipoprotein cholesterol ratio of 27 percent. All differences were statistically significant (p less than 0.01). In combined hyperlipidemic (type II B) patients, triglyceride levels decreased by 45 percent, very low-density lipoprotein cholesterol levels decreased 52.7 percent, total cholesterol levels decreased 16 percent, low-density lipoprotein cholesterol levels decreased 6 percent, and high-density lipoprotein levels increased 15.3 percent for a low-density lipoprotein cholesterol: high-density lipoprotein cholesterol ratio decrease of 13 percent. All differences were again statistically significant (p less than 0.01). In both groups of patients, the onset of the drug effect was generally rapid, with maximal total and low-density lipoprotein cholesterol level lowering achieved within four weeks in hypercholesterolemic patients and maximal triglyceride and cholesterol level lowering in hypertriglyceridemic patients achieved in two weeks. Maximum high-density lipoprotein increases occurred after four weeks in type II A patients and 12 to 16 weeks in type II B patients. Fenofibrate is a well-tolerated drug in the fibric acid series and has putatively beneficial effects on triglyceride, very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein cholesterol concentrations in both type II A and type II B hyperlipidemic patients. If the lipid hypothesis of atherosclerosis applies to the lipoprotein changes induced by fenofibrate, reductions in cardiovascular disease risk in both type II A and II B hyperlipidemic patients should result from fenofibrate treatment.

Long-term decay of serum cholesterol radioactivity: body cholesterol metabolism in normals and in patients with hyperlipoproteinemia and atherosclerosis

After the intravenous injection of labeled cholesterol, the decay of specific radioactivity of total serum cholesterol was studied in 12 patients for 15-63 wk (average, 45 wk). In some, but not all of the patients studied, the slow slope of the decay curves suggested a deviation from monoexponential behavior, and the data of the slow period of the decay of specific activity were curve fitted by two exponentials. Six patients had serum lipid values regarded as normal and six had hyperlipoproteinemia. The data were analyzed by input-output analysis and yielded the following results. Values for the input rate of cholesterol (I(T)) (the sum of dietary and biosynthesized cholesterol) showed no difference between the normals and patients with hypercholesterolemia. The size of the rapidly miscible pool of cholesterol (M(a)) was significantly higher in the group of hypercholesterolemic patients partly due to increased serum cholesterol levels. The size of the total exchangeable body mass of cholesterol (M) was higher by an average of 49 g in the patients with hypercholesterolemia as compared to normals. The remaining exchangeable mass of cholesterol (M - M(a)) of the hypercholesterolemic subjects was higher by an average of 29 g as compared to normals. These differences were statistically significant.

Long-term kinetics of serum and xanthoma cholesterol radioactivity in patients with hypercholesterolemia.

In four patients with hypercholesterolemia (type II hyperlipoproteinemia) and xanthomatosis the decay of serum cholesterol specific activity was followed for 53-63 wk after pulse labeling. Specific activity of biopsied xanthoma cholesterol was measured four times in the course of the study. The xanthoma specific activity curve crossed and thereafter remained above the serum specific activity curve. The average ratio of xanthoma to serum specific activity was 4.7 at the end of the study. The final half-time of the xanthoma decay curves was significantly greater (average: 200 days) than the slowest half-time of serum specific activity decay (average: 93 days). The data were analyzed by input-output analysis and yielded the following results. The average value for the total input rate of body cholesterol (I(T)) (sum of dietary and biosynthesized cholesterol) was 1.29 g/day. The average size of the rapidly miscible pool of cholesterol (M(a)) was 55.7 g. and of the total exchangeable body mass of cholesterol (M) 116.5 g. The average value of M - M(a) (remaining exchangeable mass of cholesterol) was 60.8 g. The derived values for exchangeable masses of cholesterol, in the present patients with marked hypercholesterolemia, were significantly larger than in a group of patients with normal serum lipids in previous studies. One of the four patients died of a sudden acute myocardial infarction 53 wk after pulse labeling. Specific activity of aortic wall and atheroma cholesterol was 3.12 times that of serum. The ratio was close to 2 for adipose tissue and spleen, and was slightly above 1 or was close to unity in most other organs studied, with the exception of brain which showed a ratio of 0.19.

Effect of Gemfibrozil on Serum Lipids in Man

The effect of gemfibrozil, a new lipid-lowering agent, was studied in 22 patients. Each patient served as his own control in a double blind study. The administration of gemfibrozil, for a period of 24 months, 1200 mg daily, reduced mean serum triglyceride levels by 45.6% (p<0.001) and mean serum cholesterol levels by 8.3% (p<0.001). Mean serum HDL cholesterol was increased by 32.3% (p<.0001) and mean serum LDL cholesterol levels were decreased by 11.4% (p<0.01). Mean serum VLDL cholesterol was decreased by 45.9% (p<0.001). A 3-hour glucose-tolerance test was done in each patient during a placebo-control period and during the administration of gemfibrozil. Mean plasma glucose was moderately increased during the administration of gemfibrozil at all points on the glucose tolerance curve, and to levels of significance at one (p<0.05) and two hours (p<0.02). There was no effect of the drug on serum immunoreactive insulin. No subjective side effects were apparent.

Familial hypercholesterolemia and xanthomatosis: Report on a rare type of kindred

Abstract A kindred with familial hypercholesterolemia and xanthomatosis is described, with results of a clinical survey and serum cholesterol determinations in thirty-three participants. The kindred includes the mating of two subjects with hypercholesterolemia without xanthomatosis, and their three children: one with xanthomatous hypercholesterolemia, another with hypercholesterolemia without xanthoma and one with normocholesterolemia. This brings to twenty-three the number of known children of similar matings found in the literature. The question whether the disease is transmitted by an incompletely dominant trait or by simple Mendelian dominance is discussed.