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Articles |
1
Otsuka America Pharmaceutical, Inc., 2440 Research Blvd., Rockville, MD 20850.
2
Pacific Biometrics, Inc. Seattle, WA 98119.
3
Clinical Research Institute of Montreal, Montreal,
Quebec, Canada H2W 1R7.
4
University of Utah, Salt Lake City, UT 84108.
5
Cardiovascular Research Institute, University of
California, San Francisco, CA 94143.
6
All results are presented in SI units. To convert from SI units to "mg/dL", multiply the values by the following conversion factors: 38.61 for cholesterol, 88.50 for triglyceride, and 0.436 for the cholesterol (VLDL-C or RLP-C)-to-total triglyceride ratio. The upper limits of the reference intervals for the ratios of VLDL-C and RLP-C to total triglyceride are 0.69 and 0.23, respectively, for the SI values (or 0.30 and 0.10, respectively, for mg/dL).
a Author for correspondence. Fax 301-721-7213; e-mail TAOW{at}MOCR.OAPI.com
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Methods: Detection of ß-VLDL by electrophoresis of VLDL was
used to define type III HLP. Twenty-eight patients with type III HLP
and 43 subjects lacking ß-VLDL were investigated. Fasting TG
concentrations were >2.26 mmol/L in all subjects. Subjects were
separated into three groups: group 1, serum total cholesterol 
5.18
mmol/L (n = 11); group 2, total cholesterol >5.18 mmol/L and TGs
between 2.26 and 9.04 mmol/L (n = 51); and group 3, TGs >9.04
mmol/L (n = 9).
Results: In group 2, a RLP-C-to-total TG molar ratio 
0.23
(0.10 when using mg/dL) and a VLDL-C-to-total TG molar ratio 0.69
(0.30 when using mg/dL) correctly classified 94% and 90% of the
subjects, respectively. The utility of the RLP-C-to-total TG ratio in
diagnosing type III HLP decreased in patients in the other two groups.
Conclusion: When used in an appropriate target population, the RLP-C-to-total TG ratio is a convenient and effective alternative to ultracentrifugal and electrophoretic methods for diagnosing type III HLP.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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apo E-2/2, an uncommon apoE phenotype seen in ~1% of the general population, has reduced affinity for receptors that are necessary for removal of remnant lipoproteins (3). When combined with other genetic or environmental factors, apoE-2 homozygotes exhibit hyperlipidemia with substantial accumulation of ß-VLDL. In these subjects, both genetic and nongenetic factors contribute to the development of overt hyperlipidemia with substantial increases of total cholesterol (TC) and triglycerides (TGs) in plasma. Compared with subjects with other types of HLP, subjects with type III HLP usually are very responsive to therapy. In most cases, life-style changes alone or in combination with treatment of a preexisting metabolic condition will normalize plasma lipid values (3). Early diagnosis of this familial disorder will therefore help physicians to select the most appropriate therapy and to identify other affected family members. It is also beneficial for these subjects to modify their life-styles to prevent premature onset of cardiovascular disease.
No single simple diagnostic test for type III HLP is available.
Electrophoretic demonstration of ß-VLDL in total VLDL (lipoproteins
with a hydrated density, d, <1.006 kg/L) is considered the
gold standard for diagnosing this disorder (1)(2)(3)(4)(5). A
VLDL-cholesterol (VLDL-C)-to-serum total TG molar ratio of 0.69
(0.30 when using mg/dL) reflects the presence of cholesterol-rich
ß-VLDL and is also considered diagnostic of type III HLP
(3)(5). apoE-2 homozygosity can confirm the
diagnosis. However, only a small fraction of apoE-2 homozygotes are
hyperlipidemic and, rarely, other mutant apoE alleles can cause
dominant forms of type III HLP (3).
To detect ß-VLDL and compute the VLDL-C-to-total TG ratio, UC must be used. UC is complex, labor-intensive, and not readily available in routine clinical laboratories. More convenient alternatives to UC and AGE are therefore needed. One convenient candidate alternative is the RLP-Cholesterol Immunoseparation Assay (RLP-Cholesterol Assay). This assay isolates remnant-like particles (RLPs) from human serum or plasma, using an immunoaffinity gel containing monoclonal antibodies to human apoA-I and apoB-100 (6)(7). These monoclonal antibodies are conjugated to Sepharose-4B beads, facilitating the separation of RLPs from other lipoproteins (HDL, LDL, nascent VLDL, and others). Cholesterol in the unbound fraction [remnant-like particle-cholesterol (RLP-C)] is then quantified by an enzymatic spectrophotometric method. It has been demonstrated that remnant lipoproteins isolated by this method resemble ß-VLDL (6)(8)(9). They are enriched in cholesteryl esters and apoE and have reduced mobility on AGE (6)(8)(9)(10)(11); they are also rapidly taken up by macrophages without modification (12). RLP-C concentrations are significantly higher in patients with type III HLP than subjects without this disorder (6)(8)(9)(11)(13). Data from these studies also suggest that the RLP-C-to-total TG ratio is also higher in subjects with type III HLP. The purpose of the current study was to compare the ability of the RLP-Cholesterol Assay with UC and AGE for the diagnosis of type III HLP in a group of hypertriglyceridemic subjects.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To compare the ability of the RLP-Cholesterol Assay with other current methods to identify patients with type III HLP, hypertriglyceridemic subjects with and without type III HLP were enrolled from two lipid clinics specialized in the treatment of familial HLP. These two clinics were at the Clinical Research Institute of Montreal (Montreal, Quebec, Canada) and at the Department of Cardiovascular Genetics Research, University of Utah (Salt Lake City, UT). All eligible subjects were 18 years and older and had a fasting serum total TG concentration between 2.26 and 9.04 mmol/L.7 They took no lipid-lowering medication for at least 6 weeks before sample collection. All subjects with type III HLP had ß-VLDL, whereas all other subjects lacked this marker. The LDL-cholesterol (LDL-C) concentration was >4.16 mmol/L in subjects classified as type IIb HLP and <4.16 mmol/L in subjects classified as type IV HLP. This study used a case-control design. Subjects with type III HLP were enrolled first. For each subject with type III HLP enrolled, one subject with type IIb HLP and one subject with type IV HLP of the same gender and similar age (± 5 years) were also enrolled. Study subjects were not enrolled on the basis of their historical serum TC value. However, subjects with type IIb or type IV HLP were selected to match the subjects with type III HLP as closely as possible in their fasting serum TG concentrations. Serum samples were collected from subjects fasted overnight and sent to Pacific Biometrics, Inc. (Seattle) for analysis. Final classification of the study subjects was based on the detection of ß-VLDL by AGE. apoE genotyping (for samples from Salt Lake City) or phenotyping (for samples from Montreal) was carried out on all samples.
Data were also reanalyzed from 749 subjects enrolled in a previously reported study carried out in 14 medical centers in the US and Canada (14). Approximately one-third of the subjects had angiographically demonstrated coronary artery disease and two-thirds were healthy controls free of coronary artery disease. Because serum lipid values were not part of the inclusion/exclusion criteria, these subjects were either normolipidemic or hyperlipidemic. Only the hyperlipidemic subgroup of the study subjects (fasting TC concentrations >5.18 mmol/L and TG concentrations >2.26 mmol/L; n = 140) was included in this secondary analysis.
All clinical study protocols and informed consent forms were approved by the local Institutional Review Boards. Informed consent forms were signed by all participating subjects.
lipid and lipoprotein analysis
Serum TC and TGs were measured by CDC-standardized enzymatic
methods. HDL-cholesterol (HDL-C) was measured after precipitation of
non-HDL lipoproteins by dextran sulfate
(Mr
50 000)-Ca2+. The RLP-Cholesterol Assay kits
were provided by Japan Immunoresearch Laboratories Co., Ltd. The
performance of this assay had been evaluated previously
(13)(14)(15).
VLDL (d <1.006 kg/L) and non-VLDL lipoproteins
(d 1.006 kg/L) were separated from serum samples by UC at
100 000g by a Beckman Ti 42.2 rotor for 4 h as
described previously (14)(16). VLDL, non-VLDL,
and unfractionated serum were then analyzed by the
REPTM Cholesterol Profile-15 Kit (a commercial
AGE device manufactured by Helena Laboratories). ß-VLDL, which has
density <1.006 kg/L (like VLDL) and ß mobility on AGE (like LDL),
can be detected by this kit. The electrophoresis pattern of each sample
was interpreted by three analysts to maintain consistency. In addition,
ß-VLDL-cholesterol (ß-VLDL-C) was also estimated as the
VLDL-C-to-total TG ratio, and quantified by using the following formula
(17):
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A VLDL-C-to-total TG ratio 0.69 (3)(4)
and an estimated ß-VLDL-C concentration >1.04 mmol/L (17)
suggest the presence of ß-VLDL and therefore type III HLP.
apoE phenotyping was performed by isoelectric focusing gel electrophoresis followed by immunoblotting of whole serum (18). apoE genotyping was performed by a restriction isotyping method (19).
statistical analysis
Differences of lipid analytes between the type III group and the
non-type III group were evaluated statistically by the Mann–Whitney
U-test because most analytes, particularly TRLs and their
remnants, have nongaussian distributions. The correlation between
different analytes was assessed by the Pearson correlation
coefficients. Linear relation between two analytes was evaluated by a
linear regression model. Differences between regression lines were
evaluated by analysis of variance. The diagnostic sensitivity,
specificity, and accuracy of each test were calculated using standard
formulas (20).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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general characteristics of study subjects
Seventy-one hypertriglyceridemic subjects, all Caucasians, were
enrolled either in Montreal or from Salt Lake City. Sixty-two subjects
(23 type III, 20 type IIb, and 19 type IV) with fasting total TG
concentrations between 2.26 and 9.04 mmol/L met the inclusion criteria
of the study protocol. The general characteristics of these 62 subjects
are shown in Table 1
. The remaining nine subjects had gross hypertriglyceridemia (TG
concentration >9.04 mmol/L) and did not meet the inclusion criteria of
the study protocol. Samples from these nine subjects were analyzed
separately to evaluate the applicability of each method in subjects
with severe hypertriglyceridemia.
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lipid profile of study subjects
As shown in Table 2
, serum TC and HDL-C concentrations of the subjects with type
III HLP and subjects with IIb HLP were similar. The serum LDL-C and
HDL-C concentrations of the subjects with type III HLP and subjects
with type IV HLP were also similar. Despite efforts to match serum
total TG concentrations of subjects without type III HLP with those
with type III HLP, the median total TG concentration was significantly
higher in those with type III HLP. Subjects with type III HLP had
significantly higher VLDL-C, estimated ß-VLDL-C, and RLP-C
concentrations than those without type III HLP.
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ratios of vldl-c and rlp-c to total tg
At any given total TG concentration between 2.26 and 9.04 mmol/L,
VLDL-C and RLP-C concentrations were higher in subjects with type III
HLP than those with type IIb or IV HLP (Fig. 1
). The linear relation between VLDL-C and total TGs was
VLDL-C = 0.89(TG) - 0.42 for subjects with type III HLP and
VLDL-C = 0.34(TG) + 0.18 for the others. The slopes of the two
linear regressions were different (P <0.01). In comparison,
the linear relation between RLP-C and total TGs was RLP-C =
0.37(TG) - 0.02 for subjects with type III HLP and RLP-C =
0.14(TG) + 0.02 for the others. The slopes of these two linear
regressions also differed significantly (P <0.05). The mean
fasting VLDL-C-to-total TG ratios were 0.80 ± 0.22 for subjects
with type III HLP and 0.39 ± 0.10 for the others (P
<0.001); the RLP-C to total TG ratios were 0.36 ± 0.14 for
subjects with type III HLP and 0.15 ± 0.05 for the others
(P <0.001). Plots of individual ratios of VLDL-C and RLP-C
to total TGs are shown in Fig. 2
.
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performance of the rlp-c assay and other methods in diagnosing type
iii hlp
On the basis of their fasting lipid profile, the 71 enrolled
hypertriglyceridemic subjects could be segregated into one of three
groups: subjects (3 type III and 8 non-type III) with isolated
hypertriglyceridemia (TC concentrations <5.18 mmol/L), subjects (20
type III and 31 non-type III) with hypercholesterolemia and with mild
to moderate hypertriglyceridemia (TC concentrations >5.18 mmol/L and
TG concentrations between 2.26 and 9.04 mmol/L), and subjects (5 type
III and 4 non-type III) with gross hypertriglyceridemia (TG
concentrations >9.04 mmol/L).
The optimal performance of the RLP-C-to-total TG ratio was achieved in
subjects with hypercholesterolemia and with mild to moderate
hypertriglyceridemia. Fifty-one subjects (20 with type III HLP and 31
without type III HLP) were in this group. All 20 subjects with type III
HLP were apoE-2 homozygotes and had detectable ß-VLDL and estimated
ß-VLDL-C concentrations >1.04 mmol/L (Table 3
). Nineteen and 16 of these subjects (95.0% and 80.0%,
respectively) also had a RLP-C-to-total TG ratio 0.23 and a
VLDL-C-to-total TG ratio 0.69, respectively. Among the 31 subjects
without type III HLP, none had detectable ß-VLDL. Thirty (96.8%) of
these subjects also had a VLDL-C-to-total TG ratio <0.69. Twenty-nine
(93.5%) had estimated ß-VLDL-C concentrations 1.04 mmol/L and a
RLP-C-to-total TG ratio <0.23. Compared with the gold standard (AGE of
VLDL), estimated ß-VLDL, the RLP-C-to-total TG ratio, and the
VLDL-C-to-total TG ratio correctly classified 49 (96.1%), 48 (94.1%),
and 46 (90.2%) of the 51 subjects (Table 3
).
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Among the 11 subjects with isolated hypertriglyceridemia, none of the 3
with type III HLP had a VLDL-C to total TG ratio 0.69. Only one had a
RLP-C-to-total TG ratio 0.23 and an estimated ß-VLDL concentration
>1.06 mmol/L. In comparison, none of the eight subjects without type
III HLP had an estimated ß-VLDL-C concentration and a VLDL-C-to-total
TG ratio exceeding the respective cutoff value. Seven also had a
RLP-C-to-total TG ratio <0.23.
Among the nine subjects with hypercholesterolemia and gross
hypertriglyceridemia, all five with type III HLP had estimated
ß-VLDL-C concentrations, VLDL-C-to-total TG ratios, and
RLP-C-to-total TG ratios greater than the respective cutoff values.
None of the four subjects without type III HLP had an estimated
ß-VLDL-C concentration or VLDL-C-to-total TG ratio greater than the
respective cutoff values. Two of these subjects, however, had a
RLP-C-to-total TG ratio 0.23.
Similar findings were observed in 140 hyperlipidemic subjects from a
previously reported study (14). Two of the 140
hyperlipidemic subjects had type III HLP evidenced by the presence of
the apoE-2/2 phenotype. In both, the RLP-C-to-total TG ratio and the
estimated ß-VLDL-C concentration exceeded their respective cutoff
values. Only one had a VLDL-C-to-total TG ratio 0.69. Three samples
from two of the subjects without type III HLP (one fasting and two
random) had TG concentrations >9.04 mmol/L. All three samples had
RLP-C-to-total TG ratios 0.23. Two had estimated ß-VLDL-C
concentrations exceeding 1.04 mmol/L. One of the two also had a
VLDL-C-to-total TG ratio 0.69. Among the 135 remaining hyperlipidemic
subjects without type III HLP, the specificity of VLDL-C-to-total TG
ratio, the RLP-C-to-total TG ratio, and the estimated ß-VLDL-C
concentration was 100%, 99%, and 96%, respectively.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although VLDL-C concentrations were significantly higher in subjects with type III HLP than in hypertriglyceridemic subjects without this disorder, there was appreciable overlap between the two groups. For this reason, the VLDL-C-to-total TG ratio, instead of VLDL-C per se, has been recommended in current practice to diagnose type III HLP (3)(4)(5). The same is true for RLP-C. Whereas VLDL-C and RLP-C concentrations alone provide information on the magnitude of the increase in remnant lipoproteins in plasma, the VLDL-C-to-total TG and the RLP-C-to-total TG ratios provide an estimate of the enrichment of TRL in cholesterol, a characteristic of ß-VLDL. This study has shown that, although RLP-C and VLDL-C were highly correlated, the RLP-C-to-total TG ratio has slightly better ability, particularly in its sensitivity, than the currently accepted marker (VLDL-C-to-total TG ratio) in diagnosing type III HLP. The "VLDL" fraction separated by UC is actually TRLs with hydrated densities <1.006 kg/L and includes chylomicrons, chylomicron remnants, VLDL, and VLDL remnants. Earlier research has shown that, compared with lipoproteins bound to monoclonal antibody JI-H, lipoproteins not recognized by this monoclonal antibody have certain physical and chemical properties of remnant lipoproteins [e.g., enrichment in cholesteryl esters and apoE, and reduced mobility on AGE (6)(8)(9)(10)(11)]. Better utility of the RLP-C-to-total TG ratio than the VLDL-C-to-total TG ratio may reflect the remnant-like properties of TRLs that are included in the RLP-C measurement.
The gold standard for diagnosing type III HLP is the detection of
ß-VLDL by AGE. To use this standard, two consecutive steps must be
taken: UC of serum lipoproteins, followed by AGE of two lipoprotein
fractions (d <1.006 and d 1.006 kg/L) together
with unfractionated serum or plasma. This adds to the cost and
complexity to the already inconvenient UC method. Furthermore,
interpretation of ß-VLDL by AGE requires an experienced individual.
Even then, the interpretation can be subjective. In comparison,
isolation of RLPs requires only a small mixing device (7)
and does not require a high degree of technical skill. Any clinical
laboratory with an accurate and precise automated, open-system design
chemistry analyzer can perform the RLP-C analysis in a relatively short
period. The ability to use previously frozen samples (14)
also offers a substantial advantage over detection of ß-VLDL. Without
the use of either AGE or UC, the RLP-C-to-total TG ratio achieved 94%
diagnostic accuracy in this case-control study (Table 3
). In a group of
140 hyperlipidemic subjects nonselective for type III HLP, the
RLP-C-to-total TG ratio correctly classified 138 of them.
Neither the VLDL-C-to-total TG ratio nor the RLP-C-to-total TG ratio
should be used to diagnose type III HLP in a general population. The
VLDL-C-to-total TG ratio has been recognized as unreliable in subjects
without hyperlipidemia (3)(4) and in subjects
with serum total TG concentrations exceeding 11.3 mmol/L
(21). As with the VLDL-C-to-total TG ratio, the
RLP-C-to-total TG ratio is more useful in patients with
hypercholesterolemia and with mild to moderate hypertriglyceridemia, a
potential indicator of substantial accumulation of ß-VLDL (Table 3
and Fig. 2
). More false-negative results occurred with calculated
values (estimated ß-VLDL-C, VLDL-C-to-total TG ratio, and
RLP-C-to-total TG ratio) in patients without hypercholesterolemia. The
accumulation of ß-VLDL in these patients is likely insufficient to
permit detection by the calculated methods. On the other hand, the
RLP-C-to-total TG ratio had more false-positive results in patients
with gross hypertriglyceridemia. Subjects with gross
hypertriglyceridemia may have type III, type I, or type V HLP. The
biochemical features of type I and type V HLP are gross increases in TG
concentrations (typically >9.04 mmol/L) and accumulation of
apoB-48-containing chylomicrons and chylomicron remnants as well as
apoB-100-containing VLDL. Use of a monoclonal antibody that recognizes
an epitope within the apoB-51 region distal to the C-terminus of
apoB-48 (7) allows apo B-48-containing lipoproteins to be
selectively enriched in the RLP fraction compared with the VLDL
fraction isolated by the UC. This may yield RLP-C-to-total TG ratios
0.23.
In conclusion, the RLP-C-to-total TG ratio provides a convenient and effective alternative to methods that require UC for diagnosing type III HLP. Optimal performance of the RLP-C-to-total TG ratio can be achieved in target populations consisting of subjects with hypercholesterolemia (TC concentration >5.18 mmol/L) and with mild to moderate hypertriglyceridemia (TG concentration between 2.26 and 9.04 mmol/L). For patients outside this target population, AGE after UC isolation of VLDL is required.
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Footnotes |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The following articles in journals at HighWire Press have cited this article:
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  E. A. Brinton, M. N. Nanjee, and P. N. Hopkins Triglyceride-rich lipoprotein remnant levels and metabolism: Time to adopt these orphan risk factors? J. Am. Coll. Cardiol., June 16, 2004; 43(12): 2233 - 2235. [Full Text] [PDF]
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 T.B. Twickler, G.M. Dallinga-Thie, J.S. Cohn, and M.J. Chapman Elevated Remnant-Like Particle Cholesterol Concentration: A Characteristic Feature of the Atherogenic Lipoprotein Phenotype Circulation, April 27, 2004; 109(16): 1918 - 1925. [Full Text] [PDF]
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 N. Sakai, Y. Uchida, K. Ohashi, T. Hibuse, Y. Saika, Y. Tomari, S. Kihara, H. Hiraoka, T. Nakamura, S. Ito, et al. Measurement of fasting serum apoB-48 levels in normolipidemic and hyperlipidemic subjects by ELISA J. Lipid Res., June 1, 2003; 44(6): 1256 - 1262. [Abstract] [Full Text] [PDF]
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 H. Hidaka, M. Tozuka, B. Meyer, K. Yamauchi, M. Sugano, T. Nakabayashi, and T. Katsuyama Characterization of Triglyceride Rich Lipoproteins with Very Light Density by Ultracentrifugation and Agarose Gel Electrophoresis using Triglyceride- and Cholesterol-Staining Ann. Clin. Lab. Sci., April 1, 2003; 33(2): 167 - 178. [Abstract] [Full Text] [PDF]
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D. J. Blom, P. Byrnes, S. Jones, and A. D. Marais Non-denaturing polyacrylamide gradient gel electrophoresis for the diagnosis of dysbetalipoproteinemia J. Lipid Res., January 1, 2003; 44(1): 212 - 217. [Abstract] [Full Text] [PDF]
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E. Campos, L. Kotite, P. Blanche, Y. Mitsugi, P. H. Frost, U. Masharani, R. M. Krauss, and R. J. Havel Properties of triglyceride-rich and cholesterol-rich lipoproteins in the remnant-like particle fraction of human blood plasma J. Lipid Res., March 1, 2002; 43(3): 365 - 374. [Abstract] [Full Text] [PDF]
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 I. Jialal and S. Devaraj Remnant Lipoproteins: Measurement and Clinical Significance Clin. Chem., February 1, 2002; 48(2): 217 - 219. [Full Text] [PDF]
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D. C. Chan, G. F. Watts, P. H. Barrett, J. C.L. Mamo, and T. G. Redgrave Markers of Triglyceride-rich Lipoprotein Remnant Metabolism in Visceral Obesity Clin. Chem., February 1, 2002; 48(2): 278 - 283. [Abstract] [Full Text] [PDF]
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 T. C. Ooi, M. Cousins, D. S. Ooi, G. Steiner, K. D. Uffelman, K. Nakajima, and I. E. Simo Postprandial Remnant-like Lipoproteins in Hypertriglyceridemia J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3134 - 3142. [Abstract] [Full Text] [PDF]
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C. Marcoux, P. N. Hopkins, T. Wang, E. T. Leary, K. Nakajima, J. Davignon, and J. S. Cohn Remnant-like particle cholesterol and triglyceride levels of hypertriglyceridemic patients in the fed and fasted state J. Lipid Res., September 1, 2000; 41(9): 1428 - 1436. [Abstract] [Full Text]
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S. Hirany, D. O'Byrne, S. Devaraj, and I. Jialal Remnant-like Particle-Cholesterol Concentrations in Patients with Type 2 Diabetes Mellitus and End-Stage Renal Disease Clin. Chem., May 1, 2000; 46(5): 667 - 672. [Abstract] [Full Text] [PDF]
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and - - - -
-).