Clinical Chemistry · 2018 · 24 citations · open access
Type III Hyperlipoproteinemia: The Forgotten, Disregarded, Neglected, Overlooked, Ignored but Highly Atherogenic, and Highly Treatable Dyslipoproteinemia
AbstractCardiovascular risk is so high in type III hyperlipoproteinemia that type III, just like heterozygous familial hypercholesterolemia (FH)2, is a treat-on-diagnosis disorder (1–3). Tragically, although severe hypercholesterolemia is easy to recognize, type III hyperlipoproteinemia cannot be diagnosed using a conventional lipid panel (4) and the original diagnostic tools—electrophoresis and ultracentrifugation—are available in only a miniscule number of clinics (1). Thus, type III cannot be diagnosed in regular clinical care using regular diagnostic tools. Moreover, while the importance of FH is recognized by all the major lipid guidelines, even the existence of type III hyperlipoproteinemia is barely acknowledged, if at all, by the same groups. Consequently, those patients with type III are lumped and dumped with all the others with mixed hyperlipidemia and the result, tragically, can be no treatment when treatment is indicated. In a wonderful paper (3), Paul Hopkins and his colleagues referred to type III hyperlipoproteinemia as the “forgotten phenotype.” Nothing has changed and so the extended title of this editorial. In this issue of Clinical Chemistry, Boot et al. (5) present the advantages of the non-HDL cholesterol (non-HDL-C)/apoB ratio as a diagnostic tool for type III hyperlipoproteinemia. I congratulate them on their work, notwithstanding that their results and conclusions, using their approach, differ at the margins from our results and conclusions using our approach (4). On reflection, it may be that we were too rigid in one direction, while they may be too rigid in another. Nevertheless, what is most important is that the work is powerfully confirmatory of that of David Marais and his colleagues from South Africa, who diagnosed type III based on the total cholesterol (TC)/apoB ratio (6). I met Dr. Marais only once, and then only briefly, but his multiple contributions to the understanding of this disorder, while working under challenging conditions with only modest support, deserve special recognition. Donald Fredrickson and his colleagues from the NIH defined type III hyperlipoproteinemia as a highly proatherogenic disorder that presents in adulthood with increased triglycerides (TG) and cholesterol due to markedly increased concentrations of abnormally cholesterol-enriched chylomicron and VLDL “remnant” particles (1). Diagnosis was based on demonstration of a broad β band on paper electrophoresis as well as demonstration by ultracentrifugation of excessively cholesterol-enriched chylomicron and VLDL remnant particles. They concluded that a plasma TG between 150 and 1000 mg/dL (1.7–11.3 mmol/L) and a VLDL-C/TG ratio ≥0.30 (for values expressed in mg/dL) was diagnostic of type III, whereas a plasma TG between 150 and 1000 mg/dL (1.7–11.3 mmol/L) and a VLDL-C/TG ratio ≥0.25 (for values expressed in mg/dL) represented “possible” type III. With time, the precise definition of type III crowded out the possible, whereas the atherogenic risk of remnant particles became generalized. The incontestable risk of remnants in type III became incontestable evidence for the risk of remnants in general, notwithstanding the multifold difference in remnant concentration between nontype III and type III (7). Moreover, the definition of remnants ranged from concentrations of apoB48 in plasma to all the cholesterol in the d < 1.006 g/mL fraction (8). But are these extensions of pathophysiological guilt epidemiologically and clinically appropriate? Although there is evidence relating increased cardiovascular risk to increased concentrations of apoB48, there is no evidence this risk is independent of total apoB. Similarly, although there is evidence demonstrating that cardiovascular risk increases as TG increase, there is no satisfactory evidence that this risk is not accounted for by VLDL apoB just as there is no satisfactory evidence that the increased cardiovascular risk associated with VLDL-C is not accounted for by VLDL apoB (7). By contrast, there is overwhelming evidence from observational studies and multiple discordance analyses that apoB is a more accurate marker of risk than LDL-C or non-HDL-C (9). There is, therefore, with the exception of type III, no reason to measure anything but apoB to estimate the total atherogenic risk due to the apoB lipoproteins. How that would simplify clinical care. Every lipid panel reports 5 numbers—TC, TG, LDL-C, non-HDL-C, and HDL-C—but in reality, except for calculating risk, virtually all clinical decisions are based on only LDL-C. No guideline has any rules for how therapeutic decisions, which are based on LDL-C, are to be modified by concurrent concentrations of HDL-C or TG. Why not end the charade of a lipid panel that must confuse almost all physicians and patients and measure, interpret, and act on one easily explainable number: apoB? However, nothing is simple 100% of the time. Type III is an exception to the apoB rule that cardiovascular risk parallels the plasma concentration of apoB, in that apoB, on average, is normal in type III (10), but cardiovascular risk is nevertheless clearly increased. In hypertriglyceridemia due to increased VLDL particles, LDL particles still account for the great majority of apoB particles. However, in type III, the ratio of the d <1.006 g/mL apoB/LDL apoB is much greater than normal because VLDL particles are not converted normally to LDL particles and neither VLDL nor chylomicron particles are cleared normally from plasma (4). Because the VLDL and chylomicron remnant particles persist so long in plasma, they become abnormally cholesterol-enriched (7). Thus, 40%–50% of all apoB particles are d < 1.006 g/mL apoB particles in type III (4). Nevertheless, the total number of apoB particles is not increased. Therefore, these abnormal cholesterol-enriched apoB remnant particles must be considerably more atherogenic than normal VLDL and LDL apoB particles. This is why, for a full diagnostic assessment, it is necessary to also measure TC and TG as well as apoB (11). Not only can type III be recognized by a diagnostic algorithm but so can other unusual disorders such as type I and type V hyperlipoproteinemia (11). On the other hand, this does not mean that remnants, if present in much smaller numbers and not cholesterol-enriched, represent a risk that is not accounted for by apoB. The strong likelihood is that 98% of the time, certainly for frontline care, apoB is all that is required. In the Boot et al. study (5), there were a small number of patients with a markedly increased apoB (apoB >120 mg/dL). It is not specifically stated but I presume that in these patients the great majority of apoB particles were d < 1.006 g/mL. On the other hand, these authors used the conventional more extreme definition for the diagnostic threshold of the VLDL-C/TG ratio, which, as we have recently reported (4), will exclude milder but otherwise still characteristic cases of type III dyslipoproteinemia. Thus, we each may have been too selective. These are important issues to resolve with further work. But they are not as important as the need to make the broader medical community aware of the present utterly tragic and utterly unnecessary failure to diagnose type III hyperlipoproteinemia. Because no population surveys using any of the newer diagnostic lipid/apoB algorithms have been carried out, there are no reliable estimates of the prevalence of the disorder. Those that are available differ importantly but, taken together, suggest type III may be at least as common as FH (2) and account for a significant minority of cases of combined hyperlipidemia. Adding to the tragedy of lost opportunities to prevent cardiovascular events and to save lives due to our failure to diagnose type III is the fact that the treatment of type III is much easier and much less expensive than is treatment of FH (2, 3). Why has type III become an orphan disorder, whereas there is limitless interest and commitment to FH? There have certainly been few individuals who have devoted time and effort to understanding and trying to educate others about this disorder. But a large part of the responsibility must fall to lipid experts and clinical chemists, who have not highlighted the shortcomings of the conventional lipid diagnostic scheme and to the guidelines that have not considered type III as a reason to measure apoB. Moreover, money often drives care. The pharmaceutical industry richly promotes education by experts about FH, a disorder for which they have new, effective, but expensive therapies, but not about type III, which can be treated with inexpensive generic drugs. Obviously, patients with FH deserve care and attention, but so do the patients with type III. Whatever the reasons that patients with type III have been so long forgotten, disregarded, neglected, overlooked, and ignored, notwithstanding that type III is a highly atherogenic but highly treatable dyslipoproteinemia, the study by Boot et al. (5) strongly reinforces the evidence that type III hyperlipoproteinemia can be diagnosed simply, accurately, and inexpensively in regular clinical care so long as apoB can be measured along with lipoprotein lipids. familial hypercholesterolemia non-HDL cholesterol total cholesterol triglyceride.
https://doi.org/10.1373/clinchem.2018.298026Journal of Atherosclerosis and Thrombosis · 2014 · 5 citations · open access
Compound Heterozygotes for a Novel Mutation, Apo E1 Nagoya (Arg142Ser) and Apo E2 (Arg158Cys), with Severe Type III Hyperlipoproteinemia and Familial Hypercholesterolemia
AbstractAIM: A patient with severe type III hyperlipoproteinemia and familial hypercholesterolemia (FH) was previously reported (Metabolism, 44,1995:460-465). In the current study, the patient's apolipoprotein (apo) E gene was analyzed. METHODS: An apo E isoform analysis was performed using isoelectric focusing and immunoblotting. In addition, after DNA preparation, a restriction fragment length polymorphism analysis and DNA sequence analysis were performed. RESULTS: The patient's apo E phenotype was E2/E1, and the genotype was ε2/ε2. The sequence analysis of the patient's DNA revealed a new variant of apo E, which involves a single substitution of one serine (AGC) for one arginine (CGC) at position 142, thereby adding one negatively charged unit to apo E2. Therefore, the patient was compound heterozygous for apo E1 (Arg142Ser) and apo E2 (Arg158Cys). CONCLUSIONS: A novel mutation, apo E1 Nagoya (Arg142Ser) in a patient with severe type III hyperlipoproteinemia with heterozygous FH was characterized. Since the presence of arginine at the amino acid residue 142 of apo E is considered to play an important role in binding to LDL receptors, the mutation apo E1 Nagoya (Arg142Ser) likely contributed to the expression of severe type III hyperlipoproteinemia in this patient.
https://doi.org/10.5551/jat.21394