Recent reports suggest a common etiopathogenetic link between FCHL and MS through the pathway of upstream stimulatory factor 1 (USF1) protein 1 and 2, members of the basic helix-loop-helix leucine zipper (bHLH-Zip) family of transcription factors, which includes the sterol regulatory element binding protein (SREBP) that has a well-established role in cholesterol and fatty acid metabolism [19
]. From a clinical perspective, these two conditions also have some similarities. In fact, high TG and/or low HDL-C plasma levels can be found in both conditions. Both are characterized by a high plasma level of small dense LDL and by a high prevalence of overweight and/or reduced glucose tolerance [9
]. A pro-thrombotic state also characterizes both conditions [20
] and both are associated with an increased cardiovascular disease risk [21
However, there are also some characteristics which help clinicians to distinguish between the two. Namely, apoB is constantly high in FCH, but not in MS [23
]. Lipid phenotype is much more variable in FCHL (more importantly, not correlated with changes in lifestyle) than in MS [24
]: lifestyle is much less relevant for FCHL prognosis than for MS, as a consequence. Inheritance of the disorder is a much more evident feature in FCH; thus, clinical and laboratory manifestations are earlier than in MS [2
From a public health point of view, the relevance of distinguishing between FCHL and MS is that the former is typically a fully inherited disease, whose prognosis is weakly modulated by lifestyle and it is even yet not evident whether the pharmacological treatments are effective in these patients (contrarily to what observed for instance in Familial Hypercholesterolemia affected ones) [25
Furthermore, because of the high prevalence of both diseases in the general population, it is also easy to note coexistence of both conditions in the same patients. Data from the US support the hypothesis that the features of metabolic syndrome are associated with a higher prevalence of cardiovascular complications in FCHL affected subjects [13
], although the absence of clear exclusion of FCHL subjects from the MS case reports allows us to suppose also that FCHL per se makes a main contribution to the strong association between MS and CHD. This appears to be true even in our population sample of strongly selected FCHL patients.
In fact, in our study MS and its main components appear not to be significantly associated with increased prevalence of early cardiovascular complications in FCHL patients, thus suggesting that the risk of developing an early cardiovascular complication is more related to the diagnosis of FCHL itself than to that of MS. Anyway, the search for MS components is relevant for the diagnosis of MS per se, but also to more correctly stratify the cardiovascular disease risk of patients who could be affected by other dyslipidemias phenotypically similar to FCHL.
However, high plasma levels of LDL-C and Lp(a) appear to be strongly associated with early cardiovascular complications in men affected by FCHL, and low HDL-C plasma levels showed an analogous association in women. We find this observation particularly interesting, because women had significantly higher baseline Lp(a) and HDL-C plasma levels than men. As for other diseases, even FCHL clinical manifestation could be strongly influenced by sex.
It may be argued that in our patient sample, MS has a relatively low prevalence compared to the general population, hypertriglyceridemia being an overlapping diagnostic factor between MS and FCH. It could be justified by an adequate selection of the FCHL patients that more specifically excluded pure MS patients.
However, our study is not prospective, so we can only find a punctual association between early cardiovascular complications and MS in FCHL patients, but not the causal role of MS in these events. This is a specific limitation of cross-sectional studies. Moreover, we did not select an age-matched sample of non FCHL-affected subjects to evaluate whether the presence of MS is more dangerous for FCHL patients than for non-FCHL subjects. Furthermore, we did not standardize the patients on the basis of their diet, which could strongly influence the lipid phenotype of both conditions [26
]. Another limitation of our study is that the OR calculation for association of MS components with cardiovascular complications was made considering the MS features as categorical, because of the inclusion of a large number of hypertensive subjects treated with antihypertensive drugs. However, the ATP III guidelines (on the basis of which MS was defined for this research) define them as categorical. Therefore, to the best of our knowledge, this is the first study to observe the role of MS features superposition on the cardiovascular complication rate in a large sample of Mediterranean FCHL subjects.
Further prospective studies have to be carried out to rigorously quantify the role of MS overlapping on the incidence of cardiovascular complications in FCHL affected subjects.