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.

Objective-Insulin resistance is associated with increased triglyceride levels, low high-density lipoprotein cholesterol, small dense low-density lipoprotein (LDL), and increased apolipoprotein B (apoB) levels, all characteristics of familial combined hyperlipidemia (FCH). Therefore, we explored the role of insulin resistance in FCH lipid phenotype expression. Key Words: apolipoprotein B Ⅲ familial combined hyperlipidemia Ⅲ insulin resistance Ⅲ obesity Ⅲ small dense low-density lipoproteins F amilial combined hyperlipidemia (FCH) is the most common familial form of hyperlipidemia, with an estimated prevalence of 1% to 3% in the general population and up to 20% of patients with premature myocardial infarction. 1 FCH was originally identified in the early 1970s as a new inherited lipid disorder, characterized by multiple phenotypes. 2 The genetic and metabolic basis of the disorder has not yet been identified. In general, FCH is thought to be caused by hepatic very lowdensity lipoprotein (VLDL) overproduction with or without impaired clearance of triglyceride (TG)-rich lipoproteins. 3 So FCH is characterized by elevated apolipoprotein B (apoB) levels and high occurrence of small dense LDL, which are both attractive new candidates to redefine FCH, as described recently. 4 Furthermore, FCH has been associated with the presence of insulin resistance and obesity. 5 Resistance to normal action of insulin is related to an excessive postprandial release of free fatty acids (FFAs) from the fat cells. High FFA levels block glucose oxidation, causing insulin resistance. 6 The high flux of FFA in the liver is the most likely driver of hepatic overproduction of TG and apoB, thereby contributing to an elevation in the concentration of VLDL. 7 Furthermore, insulin resistance contributes to decreased lipoprotein lipase activity, resulting in a reduced clearance of TG-rich lipoproteins. 8 High TG-rich lipoprotein concentrations increase the presence of small dense LDL and decrease the high-density lipoprotein (HDL) concentration. These reactions are mediated by cholesteryl-ester transfer protein 9 and hepatic lipase. 10 So insulin resistance may coincide with alterations in lipid metabolism, such as hypertriglyceridemia, increased apoB levels, low HDL levels, and a predominance of small dense LDL particles. 11 Because all these features are also characteristics of FCH, the presence of insulin resistance may be an important factor modulating FCH phenotypes. Previous studies have shown that FCH subjects are insulin resistant. [12][13][14][15][16][17][18] The aim of this study was to explore the role of insulin resistance in FCH lipid phenotype expression. Therefore, we studied in our large FCH cohort FCH subjects with different lipid phenotypes and the effect of changes in insulin resistance on intraindividual changes in lipid phenotype over a 5-year period. Furthermore, we investigated whether the elevated apoB levels and the presence of small dense LDL in FCH could be explained by the degree of insulin resistance or obesity. Metho...

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Background-Familial combined hyperlipidemia (FCH) is traditionally diagnosed by total plasma cholesterol and/or triglyceride levels above the 90th percentile adjusted for age and gender. In a recent study, we showed that the diagnosis of FCH on the basis of these diagnostic criteria was inconsistent in 26% of the subjects over a 5-year period. This result emphasizes the need for reevaluation of the diagnostic criteria for FCH. Methods and Results-A total of 32 families (299 subjects) were studied in 1994 and 1999. A subject was defined "truly" FCH when diagnosed FCH in 1994 and/or 1999 on the basis of traditional plasma lipid criteria. Additional lipid and lipoprotein parameters, including apolipoprotein B (apoB) and small, dense LDL, were measured at both time points. In total, 121 subjects (40%) were defined as truly FCH. Multivariate analysis revealed that absolute apoB values combined with triglyceride and total cholesterol levels adjusted for age and gender best predicted truly FCH. A nomogram including these parameters is provided to simply and accurately calculate the probability to be affected by FCH. Furthermore, it is shown that when percentiles of triglyceride and total cholesterol adjusted for age and gender are not available in a population, the definition of FCH can be established on the basis of hypertriglyceridemia (Ͼ1.5 mmol/L) and hyper-apoB (Ͼ1200 mg/L). Conclusions-The diagnosis of FCH is best predicted by absolute apoB levels combined with triglyceride and total cholesterol levels adjusted for age and gender and can accurately be calculated by a nomogram. This definition is also a good predictor of cardiovascular risk in

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