At a Glance
Familial combined hyperlipidemia (FCH) is the most common genetically determined dyslipoproteinemia with a prevalence of 1 in 100. FCH is characterized by an increase in cholesterolemia and/or triglyceridemia in at least two members of the same family, with intra-individual (over time) and intra-familial variability of the lipid phenotype. Increased carotid artery intima-media thickness (IMT) is a frequently observed consequence of FCH and may aid diagnosis of affected over unaffected members of the same family.
FCH carries a significantly increased risk of coronary atherosclerosis; 10-15% of patients with premature coronary heart disease (CHD) have FCH, including acute myocardial infarction survivors younger than 60 years of age). In fact, the clinical risk is similar to that associated with familial hypercholesterolemia (FH), and the two disorders may be confused. Although the genetics of this disorder are complex, FCH usually segregates with an autosomal mode of inheritance, with high penetrance, but variability in the phenotype.
FCH is distinguished from FH as follows:
Heterozygotes with FH generally have higher LDL-cholesterol (LDL-C) levels than patients with FCH, and FH heterozygotes typically have normal serum triglyceride concentration.
FCH patients often have relatives with lipoprotein abnormalities of multiple types.
Hypercholesterolemic individuals with FCH never have tendon xanthomas unless they have dysbetalipoproteinemia, whereas xanthomas are commonly observed in FH individuals.
An increased number of cholesterol-poor LDL particles is the hallmark abnormality of FCH. LDL-C levels are often unremarkable in FCH and fail to indicate the presence of elevated LDL particle concentration. The pathophysiology underlying the disorder is an overproduction of very low density lipoprotein (VLDL) ApoB and LDL ApoB particles.
High VLDL levels are a result of the overproduction of substrates, such as triglycerides and ApoB, and reduced turnover of VLDL particles. A doubling of the average transport rate of VLDL leads to the formation of small dense (VLDL and LDL) particles. These particles are susceptible to oxidation and hence are particularly atherogenic. In FCH patients with very high LDL-C, plasma levels of lipoprotein (a) may also be high and should be checked.
Because of the frequent overlap with the features of metabolic syndrome (high triglycerides, low HDL, high small dense LDL, insulin resistance, hypertension and obesity), this serious disease is often not recognized and treated. The main differences between the two conditions are:
ApoB is constantly high in FCH but not in metabolic syndrome (MS). LDL-C values are usually normal or rather low in MS.
The lipid phenotype is more variable in FCH than in MS (key point).
FCH is much more evidently influenced by inheritance and lifestyle is much less relevant to clinical manifestation and prognosis than in MS.
FCH has earlier clinical and laboratory manifestation than MS.
Low grade inflammation (high plasma hsCRP) and/or procoagulative states (e.g. high plasma fibrinogen) are more frequently associated with MS.
The following tests should be performed:
LDL and VLDL particles
small dense LDL particle
Test Results Indicative of the Disorder
First level diagnosis:
Elevations of plasma LDL-C (>160 mg/dL) and triglycerides (>200 mg/dL).
In the patient and in at least one member of the family: primary variability of the lipid phenotype (hypercholesterolemia, hypertriglyceridemia, both, or even a “normal” phenotype) evaluated on the basis of at least three consecutive (bimonthly) controls (the repetition of lipid analysis to define a diagnosis of dyslipidemia follows international guidelines). The higher the number of family members’ samples, the better the diagnostic sensitivity.
Second level diagnosis:
Elevated ApoB (>125 mg/dL) is one of the best diagnostic and prognostic factors for FCH.
Preponderance of small dense LDL particles.
Total cholesterol will be marginally increased.
HDL-C is typically mildly depressed.
Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
The laboratory manifestation of FCH may remain relatively silent until some events occur. In particular, body weight increase appears to be strongly related to lipid modification that could be observed in FCH patients. Indeed, waist-to-hip ratio appears the best determinant of hyperlipidemia (especially hypertriglyceridemia) in FCH patients. This could be related to insulin resistance.
What Lab Results Are Absolutely Confirmatory?
There is no specific laboratory or clinical marker of FCH.
Because both LDL-C and triglycerides are not necessarily high in FCH patients, it may be that values considered “borderline high” by the ATP III guidelines (LDL-C >130 mg/dL and/or TG >150 mg/dL) could be useful to evaluate the intra-individual variability of the phenotype. Lipid levels should be monitored closely, in addition to clinical markers of coronary heart disease (e.g. IMT).
The spontaneous variability of lipid phenotype appears associated with an increased risk of cardiovascular disease. Family history and laboratory values should be used in conjunction to make the diagnosis of FCH. Family members of patients diagnosed with FCH should be more closely monitored from the onset of clinical symptoms and laboratory abnormalities associated with FCH as these may be precipitated by environmental factors or secondary causes.
Laboratory results for LDL-C and triglycerides are generally not falsely affected by medications or supplements, but changes that occur in values reflect actual changes in these values. Statin drugs may markedly lower LDL-C but may not reduce LDL particles to a level that would be considered to be protective. This may be observed in either FCH or the metabolic syndrome. In such cases, apoB and or LDL particle concentration should be measured in combination with LDL-C values or should be measured after LDL-C is treated to goal, to insure that the number of atherogenic particles have been adequately reduced.
Although statin drugs do reduce total numbers of LDL particles, they do not typically alter the size of LDL particles. Agents such as niacin and fibric acid drugs may result in changes in the LDL size distribution, resulting in larger and fewer particles, lowering apoB and LDL particles more effectively than they reduce LDL-C.
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- At a Glance
- Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?
- What Lab Results Are Absolutely Confirmatory?