Familial Combined Hyperlipidemia Group Research Articles

Relationship Between Total Serum Bilirubin Levels and Carotid and Femoral Atherosclerosis in Familial Dyslipidemia.

Bilirubin is a potent antioxidant that has been inversely related to cardiovascular disease. There is little information on serum total bilirubin (TB) in relation to atherosclerosis in familial dyslipidemia. We assessed the association between TB and carotid and femoral atherosclerosis in this high-risk group. We evaluated 464 individuals with familial dyslipidemia (56% men; median age, 48 years), 322 with familial hypercholesterolemia, and 142 with familial combined hyperlipidemia. Carotid and femoral arteries were imaged bilaterally with a standardized ultrasonographic protocol. Mean and maximum intima-media thickness and plaque presence (≥1.2 mm) and height were recorded. Cross-sectional associations between TB and atherosclerosis variables were investigated in multivariable-adjusted models, including lipid values and hypolipidemic drug use. Inflammatory markers (C-reactive protein, total leukocyte count, and lipoprotein[a]) were also determined. Increasing TB levels were associated with decreasing intima-media thickness of all carotid segments (P<0.05, all). TB also related to carotid plaque, present in 78% of individuals, and to plaque burden (≥3 plaques), with odds ratios (95% confidence interval) 0.59 (0.36-0.98) and 0.57 (0.34-0.96) for each increase of 0.5 mg in TB, respectively. Findings were confirmed in a validation cohort of 177 subjects with nonfamilial dyslipidemia. Only the familial combined hyperlipidemia group, with higher inflammation-related markers, showed an inverse association between TB and femoral plaque height (β=-0.183; P=0.030). TB was inversely and independently associated with carotid plaque burden in familial and nonfamilial dyslipidemia. These findings support the use of TB as a biomarker of atherosclerosis in this high-risk group.

P.1.e.016 Cortisol awakening response and cerebral serotonin transporter binding

The presence of insulin resistance in 20 male nondiabetic patients with familial combined hyperlipidemia (FCH) and 20 controls of similar age and body mass index (BMI) was investigated using the minimal model method modified by the administration of insulin and an oral glucose tolerance test. The peripheral sensitivity of insulin, expressed as the insulin sensitivity index (Si), was 1.91 ± 1.05 and 2.86 ± 1.19 × 10−4 · min−1 · mU/L in FCH patients and controls, respectively (P < .01), and the corresponding value for the peripheral utilization of glucose independently of insulin (Sg) was 1.70 ± 1.13 in FCH patients and 2.35 ± 0.60 × 10−2 · min−1 in controls (P < .02). In the FCH group, the Si value correlated significantly (P < .05) with the waist to hip ratio (WHR), plasma triglycerides (TG), free fatty acids (FFA), and the area under the curve of glucose (AUCg) and insulin (AUCi). In the control group, the correlation also reached statistical significance (P < .05) with age, BMI, WHR, blood pressure, TG, AUCg, and AUCi. Subgrouping the subjects with respect to central obesity defined as a WHR of 0.95 or greater, we observed lower Si values in obese and non-obese FCH subjects relative to controls (P < .02). The mean Si value in obese subjects was significantly lower than in non-obese FCH subgroups (1.40 ± 0.79 v 2.68 ± 0.95 × 10−4 · min−1 · mU/L, respectively, P < .01). In conclusion, a higher degree of insulin resistance relative to control values appears to be an integral part of the metabolic derangements observed in FCH, and central-trunk obesity exacerbates the insulin resistance syndrome.

FABP4 plasma levels are increased in familial combined hyperlipidemia

FABP4 plasma levels are increased in familial combined hyperlipidemia

Altered vascular responses to circulating angiotensin II in familial combined hyperlipidemia

Patients with familial combined hyperlipidemia (FCHL) are at increased risk of hypertension and cardiovascular disease. We examined if patients with FCHL have altered microvascular and macrovascular responses to angiotensin II, a principal mediator of the renin-angiotensin-aldosterone system. Sixteen patients with FCHL and 16 healthy controls were investigated before, during and after a 3 h intravenous infusion of angiotensin II (10 ng/kg/min). Forearm skin microcirculation was studied by laser Doppler fluxmetry during rest and local heating to 44 degrees C (microvascular hyperemia). Baseline systolic blood pressures were 129 +/- 13 and 123 +/- 12 mmHg in FCHL patients and controls (P = 0.11), respectively. Angiotensin II elicited a greater systolic blood pressure response in the FCHL group (+32 +/- 13 mmHg) than in the control group (+20 +/- 11 mmHg; P < 0.001). At 3 h angiotensin II infusion, microvascular hyperemia increased in the controls (P < 0.001), whereas microvascular hyperemia was unchanged in the FCHL patients (P < 0.01, between groups). In healthy individuals, a 3 h intravenous infusion of angiotensin II enhances heat-induced microvascular hyperemia. In FCHL, this microvascular hyperemia is impaired and the systolic blood pressure response is increased. A reduced microvascular dilatation capacity in FCHL may contribute to the observed blood pressure elevation and promote development of micro- and macrovascular complications.

Metabolic syndrome prevalence and characteristics in Greek adults with familial combined hyperlipidemia

Familial combined hyperlipidemia (FCH) is closely related with metabolic syndrome (MetSyn), and coronary artery disease (CAD) is positively associated to MetSyn and FCH. In this study, we evaluated the prevalence of MetSyn and its components between patients with FCH and a control group. We also investigated the role of MetSyn and diabetes mellitus (DM) on the incidence of CAD within the FCH group. Our study population consisted of 463 male and 243 female patients with FCH who were not receiving any hypolipidemic treatment, and 1128 men and 1154 women who came from the same geographical region. The prevalence of MetSyn was 42% and 19.8% among FCH subjects and controls, respectively, whereas MetSyn increased with age in both groups. The prevalence of CAD was 15.3% in the FCH group. Moreover, after dividing FCH patients into 3 subgroups, with and without MetSyn and with DM, CAD prevailed at a percentage of 15.2%, 11.1%, and 26.5%, respectively. However, statistically significant differences in the prevalence of CAD were observed only between FCH subjects with DM compared with the other 2 subgroups, even when an adjustment for age, sex, and smoking was conducted. People with FCH and MetSyn differed in several anthropometric, biochemical, and clinical characteristics, compared with the non-MetSyn subgroup of FCH. MetSyn is more prevalent in the FCH than in the control group. Among subjects with FCH, only DM was significantly associated with an increase in the prevalence of CAD in this subgroup compared with FCH individuals with or without MetSyn.

Plasma homocysteine in subjects with familial combined hyperlipidemia

Familial combined hyperlipidemia (FCH) is characterised by hypercholesterolemia and/or hypertriglyceridemia and associated with an increased risk of cardiovascular disease (CVD). The plasma lipid and lipoprotein levels in subjects with FCH are relatively moderately elevated and do not fully explain the increased risk of CVD. Hyperhomocysteinemia is a disorder of methionine metabolism and also a well-known independent risk factor for CVD. We investigated whether subjects with FCH have higher plasma homocysteine concentrations than controls, and whether homocysteine contributes to the increased risk of CVD in FCH. Furthermore we evaluated whether parameters of lipid and lipoprotein metabolism and/or insulin resistance are associated with the homocysteine level. In total 667 subjects, including 161 subjects with FCH, 109 spouses who referenced as control group and 397 normolipidemic relatives were studied. FCH was defined by the presence of plasma total cholesterol and/or triglyceride levels above the 90th percentile adjusted for age and gender. The mean homocysteine concentration of the FCH group did not significantly differ from the control group. The risk for CVD due to hyperhomocysteinemia in subjects with FCH was not higher than in subjects without FCH. No associations were observed between plasma homocysteine concentration and plasma lipid and lipoprotein levels, including small dense low density lipoprotein, nor between homocysteine concentration and insulin resistance.

Diagnosis of familial combined hyperlipidemia based on lipid phenotype expression in 32 families: results of a 5-year follow-up study.

Familial combined hyperlipidemia (FCH) is characterized by a variable expression of hypercholesterolemia and/or hypertriglyceridemia. We evaluated the variability in lipid phenotype expression over a 5-year period and studied factors affecting the lipid phenotype expression. A total of 32 families (299 subjects) were studied in 1994 and in 1999. Subjects were classified as having FCH when total cholesterol and/or triglyceride levels exceeded the 90th percentile adjusted for age and sex. In 1994, 93 (31%) of the 299 subjects were affected, whereas 206 (69%) of the subjects were unaffected relatives. In 1999, a diagnosis of FCH was consistent in 69 (74%) of the 93 subjects. So, 26% of the FCH subjects in 1994 showed a sporadic normolipidemic pattern (ie, total cholesterol and/or triglycerides <90th percentile) in 1999. Among the 206 unaffected relatives in 1994, 178 (86%) remained unaffected in 1999, and 28 (14%) developed an FCH lipid phenotype. Multiple regression analysis showed that sex (odds ratio 2.03, 95% CI 1.09 to 3.87; P=0.03) and body mass index (odds ratio 1.14, 95% CI 1.05 to 1.24; P<0.01) significantly contributed to the variability in lipid phenotype expression. Thus, a diagnosis of FCH, based on plasma total cholesterol and/or triglyceride levels, is consistent in only 74% of the subjects over a 5-year period. Two other major characteristics of our FCH group, compared with the unaffected relatives, included elevated apolipoprotein B (apoB) levels and the presence of small dense low density lipoprotein (LDL), as reflected by a low value of the parameter K (apoB 1461 +/- 305 versus 997 +/- 249 mg/L, respectively [P < 0.001]; K value -0.22 +/- 0.19 versus -0.02 +/- 0.19, respectively [P < 0.001]). We now report that the apoB concentration and the K value show less variability in time and are more consistently associated with FCH, inasmuch as affected FCH subjects, compared with the unaffected relatives, persistently show a higher apoB level and a lower value of parameter K, reflecting small dense LDL, even when they present a sporadic normolipidemic pattern. In conclusion, our results emphasize the need for reevaluation of the diagnostic criteria for FCH. We demonstrate that apoB and small dense LDL are attractive new candidates for defining FCH. Further studies are indicated to evaluate the role of apoB and small dense LDL as diagnostic criteria for FCH.

Relationship of insulin sensitivity and ApoB levels to intra-abdominal fat in subjects with familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is one of the most common familial dyslipidemias associated with premature heart disease. Subjects with FCHL typically have elevated apolipoprotein B (apoB) levels, variable elevations in cholesterol and/or triglycerides, and a predominance of small, dense, low density lipoprotein particles. It is thought that insulin resistance is important in the expression of the combined hyperlipidemia phenotype. To further characterize the relationship between insulin resistance and increased apoB levels, 11 subjects from well-characterized FCHL families and normal control subjects matched for weight and/or age underwent measurement of intra-abdominal fat (IAF) and subcutaneous fat (SQF) by CT scan, insulin sensitivity (Si) by the frequently sampled intravenous glucose tolerance test, and lipoprotein levels. Body mass index and IAF were higher and Si was lower (more insulin resistant) in the FCHL group than in the age-matched group, but the values were similar in the FCHL group and the age- and weight-matched control group. When the relationship between body fat distribution and Si was tested with multiple linear regression, only IAF was significantly correlated with Si after the addition of SQF and body mass index as independent variables. For any level of insulin sensitivity or IAF, however, apoB levels remained higher in the FCHL subjects than in the control groups. In conclusion, in FCHL, visceral obesity is an important determinant of insulin resistance. Visceral obesity and insulin resistance, however, do not fully account for the elevated levels of apoB in this disorder, and this study provides physiological support for separate, but additive, genetic determinants in the etiology of the lipid phenotype.

Mutations of the human hepatic lipase gene in patients with combined hypertriglyceridemia/hyperalphalipoproteinemia and in patients with familial combined hyperlipidemia.

Hepatic lipase is an enzyme which hydrolyzes triglycerides from plasma lipoproteins and thus takes part in the metabolism of intermediate density lipoproteins and high-density lipoproteins. The search described here concentrated on mutations of the HL gene in 129 patients with combined hypertriglyceridemia/hyperalphalipoproteinemia and in 184 members of 19 families with familial combined hyperlipidemia. Controls were 100 subjects with favorable lipid values (age 46-51 years). Mutation screening and analysis were performed by temperature-gradient gel electrophoresis, allele-specific restriction genotyping, and sequencing. Six different missense mutations and four different silent mutations were found in the HL gene. The alleles Phe-267 and Gln-343 were detected only once in the patient group with hypertriglyceridemia and hyperalphalipoproteinemia and were not detected in the control group. The allele Met-383 was rare in both patients and controls. We found 9.3% of the patients and only 3.0% of controls to be carrying the Val-73-Met missense mutation. The allele Phe-334 was found in 5.43% of patients and in 2.0% of controls. The difference between the frequencies of these alleles was significant between male patients and male controls (Met-73 P=0.044; Phe-334 P=0.047). Also, the summarized odds ratio of 3.28 (95% confidence interval 1.23-8.73) demonstrates that mutation carriers are significantly more prevalent in the patients. Fifteen carriers of the Met-73 allele were found in six families of the familial combined hyperlipidemia group. Furthermore, six carriers of the Phe-334 allele were found in three families of the same group. In comparison to the controls the summarized odds ratio of 2.45 (95% confidence interval 0.89-6.71) barely missed the level of significance. The linkage between genotype and phenotype was incomplete. These results show an association of the missense mutations Val-73-Met and Leu-334-Phe as susceptibility alleles for combined forms of hyperlipidemia.

Evidence against alterations in Lecithin:cholesterol acyltransferase (LCAT) activity in familial combined hyperlipidemia.

Elevated concentrations of plasma cholesterol and triglycerides are characteristic of familial combined hyperlipidemia (FCHL) which may also present with reduced high density lipoprotein (HDL) cholesterol concentrations. Lecithin:cholesterol acyltransferase (LCAT) plays a key role in reverse cholesterol transport by converting unesterified cholesterol to cholesterol ester in the process of maturation of HDL in the presence of its activator, apolipoprotein (apo) A-I. We hypothesised that alterations in LCAT activity or plasma concentrations or gene sequence of apo A-I could influence HDL metabolism in these patients. We studied cholesterol concentrations of high density lipoprotein subfractions and LCAT activity in 25 FCHL subjects and 48 controls. Total HDL (p=0.018) and HDL2 (p=0.008) were significantly decreased in the FCHL group compared with controls. After analyses with adjusted data only HDL2 remained significantly decreased in the FCHL group (p=0.050). The LDLc/HDLc and A-I/HDLc ratios were significantly elevated in the FCHL group (p <0.0001), the latter suggesting the existence of compositional differences in the HDL particles of the FCHL individuals. LCAT activity assessed in the FCHL (19.94+/-3.95 nmol/ml per h) and control (20.13+/-6.86 nmol/ml per h) groups showed no statistically significant differences. A significant positive correlation of LCAT activity with total HDL (r=0.42), HDL3 cholesterol (r=0.46) and apolipoprotein A-I (r=0.47) was observed in affected subjects but not in controls. An association between a Ga(-75)-A variation in the promoter region of the apo A-I gene and elevated concentrations of apo A-I (p=0.009) and apo C-III (p=0.041) was observed. This association was strongly influenced by the status of the subject providing further evidence for a regulatory role of this genetic region in the expression of FCHL. Our data suggests that LCAT activity is normal in FCHL and, therefore, does not account for the abnormalities observed in these patients essentially with regard to the HDL2 subfraction.

A study of insulin resistance using the minimal model in nondiabetic familial combined hyperlipidemic patients

The presence of insulin resistance in 20 male nondiabetic patients with familial combined hyperlipidemia (FCH) and 20 controls of similar age and body mass index (BMI) was investigated using the minimal model method modified by the administration of insulin and an oral glucose tolerance test. The peripheral sensitivity of insulin, expressed as the insulin sensitivity index (Si), was 1.91 ± 1.05 and 2.86 ± 1.19 × 10 −4 · min −1 · mU/L in FCH patients and controls, respectively ( P < .01), and the corresponding value for the peripheral utilization of glucose independently of insulin (Sg) was 1.70 ± 1.13 in FCH patients and 2.35 ± 0.60 × 10 −2 · min −1 in controls ( P < .02). In the FCH group, the Si value correlated significantly ( P < .05) with the waist to hip ratio (WHR), plasma triglycerides (TG), free fatty acids (FFA), and the area under the curve of glucose (AUCg) and insulin (AUCi). In the control group, the correlation also reached statistical significance ( P < .05) with age, BMI, WHR, blood pressure, TG, AUCg, and AUCi. Subgrouping the subjects with respect to central obesity defined as a WHR of 0.95 or greater, we observed lower Si values in obese and non-obese FCH subjects relative to controls ( P < .02). The mean Si value in obese subjects was significantly lower than in non-obese FCH subgroups (1.40 ± 0.79 v 2.68 ± 0.95 × 10 −4 · min −1 · mU/L, respectively, P < .01). In conclusion, a higher degree of insulin resistance relative to control values appears to be an integral part of the metabolic derangements observed in FCH, and central-trunk obesity exacerbates the insulin resistance syndrome.

Effects of different phenotypes of hyperlipoproteinemia and of treatment with fibric acid derivatives on the rates of cholesterol 7 alpha-hydroxylation in humans.

Little is known about the relationships between hyperlipidemia and bile acid metabolism. However, hypolipidemic treatment with fibric acid derivatives has been shown to increase biliary cholesterol secretion, presumably by reducing bile acid synthesis. To clarify such relationships, we investigated the effects of different hyperlipoproteinemic conditions and of treatment with fibric acid derivatives on the rates of cholesterol 7 alpha-hydroxylation (the limiting step of bile acid synthesis) in humans. We studied 10 patients (aged 36 to 68 years) with lipoprotein phenotype IIa and with a clinical diagnosis of heterozygous familial hypercholesterolemia, a condition of reduced activity of LDL receptors, and 11 patients (aged 48 to 70 years) with lipoprotein phenotype IIb or IV and clinical diagnosis of familial combined hyperlipidemia, a condition probably related to increased hepatic lipoprotein synthesis. Cholesterol 7 alpha-hydroxylation rates were assayed in vivo by tritium release assay after an intravenous injection of [7 alpha-3H]cholesterol. The results were compared by ANOVA to the values obtained in a group of 28 normolipidemic patients (aged 34 to 83 years), with age as the covariate. Six patients were also studied after treatment with gemfibrozil (900 to 1200 mg/d for 6 to 8 weeks) and 5 patients were studied after treatment with bezafibrate (400 mg/d for 6 to 8 weeks). Hydroxylation rates were 0.82 +/- 0.22 mmol/d in the familial hypercholesterolemia group and 1.30 +/- 0.47 mmol/d in the familial combined hyperlipidemia group (P < .05 between the two groups and between patients with familial combined hyperlipidemia and control subjects; P = NS between patients with familial hypercholesterolemia and control subjects, as determined by ANOVA).(ABSTRACT TRUNCATED AT 250 WORDS)

Stable isotopes show a direct relation between VLDL apoB overproduction and serum triglyceride levels and indicate a metabolically and biochemically coherent basis for familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) may be genetically and metabolically more heterogeneous than previously thought. A consistent feature is an increase in circulating very-low-density lipoprotein (VLDL) apolipoprotein (apo) B, which could be due to either an increase in apoB production or a decrease in its catabolism. Therefore, we directly measured VLDL apoB production in the postabsorptive state in seven FCHL subjects (four male, three female) and seven normal control subjects (three male, four female) by using L-[1-13C]leucine as an endogenous label. Mean age and body mass index did not differ significantly between the two groups. The mean total cholesterol levels were 4.7 +/- 0.8 and 8.8 +/- 1.6 mmol/L (+/- SD, P < .01) and the mean triglyceride levels were 0.84 +/- 0.14 and 3.30 +/- 1.10 mmol/L (+/- SD, P < .01) in the control and FCHL groups, respectively. Although the fractional production rate of VLDL apoB was 38% lower in the FCHL group than in the control subjects (0.11 +/- 0.03 versus 0.18 +/- 0.02 pool/h; mean +/- SD, P < .01), its absolute production rate was 2.7 times greater (534 +/- 193 micrograms/kg per hour in FCHL versus 196 +/- 71 micrograms/kg per hour in control subjects; mean +/- SD, P < .01). There was a linear relation (r = 0.8, P = .03) between triglyceride levels and the VLDL apoB production rate in FCHL, the slope of which indicated a similar VLDL triglyceride-to-apoB ratio in the FCHL and control groups. We conclude that FCHL is a metabolically coherent disorder and that the increase in circulating apoB and triglyceride levels in FCHL is due to secretion of an increased number of VLDL particles, each containing, on average, a normal amount of triglyceride and one molecule of apoB.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of cholestyramine in the treatment of children with familial combined hyperlipidemia

We studied the effectiveness of and compliance with the use of cholestyramine in children with heterozygous familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCHL). During a 10-year period, 673 children (aged 10.5 +/- 4.0 years) were referred for evaluation of hyperlipidemia, of whom 87 (36 with FH; 51 with FCHL) were treated with cholestyramine (8 to 24 gm/day). In both groups, total cholesterol, low-density lipoprotein (LDL)-cholesterol, and apolipoprotein B levels were significantly reduced after cholestyramine use. In those with FH, plasma LDL-cholesterol levels decreased from 258 +/- 35 mg/dl (6.67 +/- 0.90 mmol/L) to 190 +/- 31 mg/dl (4.91 +/- 0.80 mmol/L); in those with FCHL, LDL-cholesterol levels dropped from 207 +/- 40 mg/dl (5.35 +/- 1.03 mmol/L) to 141 +/- 35 mg/dl (3.64 +/- 0.90 mmol/L). High-density lipoprotein-cholesterol levels were not significantly changed after cholestyramine use in either group. In the FCHL group, plasma triglyceride levels increased significantly from 81 +/- 35 mg/dl (0.92 +/- 0.40 mmol/L) to 134 +/- 42 mg/dl (1.52 +/- 0.48 mmol/L). Seven patients were lost to follow-up; 18 discontinued the medication within 1 month. Of the remaining 62 children, 59 had a good response to the drug. Of the 62 patients, 52 discontinued the medication after 21.9 +/- 10 months. Adverse effects included foul taste (73%), nausea with bloating (18%), and constipation. Cholestyramine is effective in reducing LDL-cholesterol levels in children with inherited hyperlipidemia, but the majority of children will not comply with its long-term use.