Reiko Ikeuchi

Coexisting type III hyperlipoproteinemia and familial hypercholesterolemia: A case report

A 39-year-old man presented with type III hyperlipoproteinemia in association with heterozygous familial hypercholesterolemia (FH). He had extensive tuberous xanthomas over the knees and elbows and xanthomas in the Achilles tendons. He also had palmar xanthomas. He exhibited severe hypercholesterolemia and hypertriglyceridemia. This patient was heterozygous for FH, as evidenced by low low-density lipoprotein (LDL) receptor function on lymphocytes, and had type III hyperlipoproteinemia, as determined by apolipoprotein (apo) E phenotype 2/2 in isoelectric focusing of the E isoproteins and the presence of a broad beta band on electrophoresis. Because therapy consisting of diet restrictions and lipid-lowering agents such as clinofibrate and niceritrol did not decrease serum total cholesterol ([TC] 15.26 mmol/L) and triglyceride ([TG] 10.79 mmol/L) levels effectively, the patient underwent plasmapheresis once every 2 weeks using a dextran sulfate-cellulose column. Repeated plasmapheresis markedly reduced serum TC and TG and induced complete regression of the palmar xanthoma after 6 months. The severity of tuberous xanthomas on the knees and elbows was reduced after 2.5 years. After plasmapheresis, TC decreased to 1.94 mmol/L from 10.40 mmol/L and TG decreased to 0.33 mmol/L from 7.90 mmol/L. Plasmapheresis performed with a dextran sulfate-cellulose column was highly effective in removing the lipoprotein-remnant particles in this patient, leading to generalized improvement in the lipoprotein profile.

Changes of HDL subfraction concentration and particle size by intralipid in vivo.

The effects of the artificial triglyceride-phospholipid emulsion (10% intralipid) on HDL subfraction were studied in vivo. After a 14-h fast, subjects received intralipid via a 4-h infusion. Serum lipoproteins were analyzed before and at 4 and 6 h after the start of the infusion. At 4-h the following acute changes by infusion were observed. Triglyceride, phospholipid, free cholesterol, and esterified cholesterol in chylomicrons and VLDL increased. HDL2 as well as triglyceride, phospholipid, free cholesterol and protein within the HDL2 increased, while HDL3 decreased. An increase in HDL3 triglyceride was observed. The masses of apo A-I and A-II in the HDL2 density interval rose while these parameters fell in HDL3. There were decreases of apo C-II and C-III in the HDL subfractions and elevations in chylomicrons and VLDL. The particle size of the HDL subfractions increased. However, most of these acute changes at 4 h tended to disappear by 6 h. These results suggest that there is exchange of lipids and reversible transfer of apo C-II and C-III between HDL subfractions and intralipid, and conversion of HDL3 to HDL2 followed by the reverse conversion of HDL2 to HDL3 as the synthetic emulsion is cleared from the plasma.

Increased serum triglyceride clearance, unchanged cholesteryl ester transfer protein activity, and elevated HDL cholesterol during treatment of hypertriglyceridemia with bezafibrate

The effects of bezafibrate on lipid metabolism were evaluated in 22 patients with type IIb or type IV hypertriglyceridemia. Bezafibrate 400 mg/d was administered for 8 weeks. A fat emulsion tolerance test (FETT) to evaluate serum triglyceride (TG) clearance (fractional removal rate = K2) and measurement of cholesteryl ester transfer protein (CETP) activity were performed before bezafibrate administration and after the 8-week treatment period using blood samples obtained after overnight fasting. Statistically significant reductions were observed in serum TG (P < 0.01), apolipoprotein (apo) B (P < 0.01), apo C-II (P < 0.05), apo C-III (P < 0.001), and apo E (P < 0.05). Significant increases were seen in high-density lipoprotein cholesterol (HDL-C) (P < 0.001), apo A-I (P < 0.001), and apo A-II (P < 0.001). K2 was significantly elevated (P < 0.001). CETP activity declined slightly, but the change was not statistically significant. Strong positive correlations were evident between the absolute value of increased K2 and the increase in both HDL-C (r = .67, P < 0.005) and apo A-I (r = .53, P < 0.05). It can be inferred from these findings that the bezafibrate-induced reduction in serum TG and increase in HDL-C observed in patients with hypertriglyceridemia arise from an acceleration in TG-rich lipoprotein metabolism.

Fractional removal rate of fat emulsion (K2) remains to be low in APOE3/3 phenotype subjects with serum triglyceride level above 180mg/dl.

The relation between fractional catabolic rate (K2) of an intravenously injected fat emulsion, Intralipid, and the level of serum triglyceride (TG) was evaluated to cast light on TG-rich lipoprotein metabolism in 182 subjects who were homozygotes for the most common form of apoE3/3. Both normolipidemic individuals and primary hyperlipidemic patients were included. To assess the influence of variation in the apoE phenotype on fat emulsion metabolism, 25 subjects with the apoE 4/3 phenotype and 21 with apoE 3/2 phenotype were also evaluated. In the apoE 3/3 subjects, K2 decreased with increasing TG level up to 180mg/dl, but above 180mg/dl, K2 remained at a constant level. This TG value was therefore concluded to be a cut off beyond which the TG-dependent decrease in K2 disappeared. No apparent correlation between K2 and serum TG was observed in subjects with apoE 4/3 or 3/2 phenotypes. In subjects with TG above 180mg/dl, presumably both accelerated synthesis and limited removal are involved in the development of their hypertriglyceridemia. Since K2 demonstrated little change with increase of TG over 180mg/dl in apoE 3/3 subjects, we concluded that the capacity to catabolize fat emulsion reaches a kinetic saturation. The TG value of 180mg/dl may be a physiological significance. The relation between K2 and TG was specific in apoE 3/3, as it was not observed in subjects having apoE 4/3 or 3/2 phenotypes.

Increased Serum Triglyceride Clearance and Elevated High-Density Lipoprotein 2 and 3 Cholesterol During Treatment of Primary Hypertriglyceridemia with Bezafibrate

BACKGROUND Hypertriglyceridemia accompanied by low levels of high-density lipoprotein cholesterol (HDL-C) is a risk factor for coronary artery disease. High-density lipoprotein 2 (HDL2) and 3 (HDL3) are believed to suppress the progress of atherosclerosis through reverse cholesterol transport. As a result, peripheral tissues can be protected against excessive accumulation of cholesterol. Although bezafibrate is known to accelerate the increase of HDL-C, results are not standardized regarding increases of HDL3 and HDL2 subfractions. OBJECTIVE This study assessed the effects of bezafibrate on serum triglyceride (TG) fractional clearance rate (K2) and HDL2 and HDL3 cholesterol (HDL2-C and HDL3-C, respectively) levels in patients with primary hypertriglyceridemia (serum TG ≥150 mg/dL). METHODS Outpatients with primary hypertriglyceridemia were enrolled in this 8-week study conducted at the Third Department of Internal Medicine, Nagoya City University Hospital (Nagoya, Japan). Oral bezafibrate was administered at a dose of 400 mg/d (200-mg tablet BID, morning and evening) for 8 weeks. After 8 weeks, serum levels of total cholesterol (TC), TG, HDL-C, HDL2-C, and HDL3-C were measured. A fat emulsion tolerance test to assess K2 and measurements of plasma lipoprotein lipase (LPL) mass, LPL activity, and hepatic triglyceride lipase (HTGL) activity in postheparin plasma were performed before bezafibrate administration and after the course of treatment. RESULTS Sixteen patients (10 men, 6 women; mean [SD] age, 54 [12] years [range, 30-69 years]; mean [SD] body mass index, 23 [2] kg/m(2)) entered the study. The following findings were observed in male and female patients after 8 weeks of treatment. A statistically significant reduction was observed in mean serum TG level (P<0.01). Significant increases were seen in HDL-C, HDL2-C, and HDL3-C (all P<0.01), K2 (P<0.01), and in plasma LPL mass (P<0.01) and LPL activity (P<0.05). TC level and HTGL activity did not change significantly. No adverse effects related to the use of bezafibrate were documented. CONCLUSIONS In this study, bezafibrate treatment resulted in significant decreases in serum TG level and significant increases in HDL2-C and HDL3-C levels and plasma LPL mass and activity. We hypothesize that bezafibrate may increase HDL3-C by promoting TG-rich lipoprotein catabolism and may increase HDL2-C by promoting the conversion of HDL3 to HDL2.