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Technical Briefs |
1
The Curacel Institute of Medical Research, 14/1645 Ipswich Rd., Rocklea Queensland 4106, Australia;
2
Lipid Metabolism Laboratory, Department of Surgery, University of Queensland, Royal Brisbane Hospital, Herston Queensland 4029, Australia;
3
Wesley Medical Centre, Auchenflower Brisbane Queensland 4060, Australia;
a author for correspondence: fax 61-7-3274-4453
We wished to investigate the mechanism of decreased serum
vitamin K1 after bone fractures. Vitamin
K1 plays a role in bone formation because it is
required as a cofactor for the transformation of glutamic acid (Glu)
residues on proteins to 
-carboxyglutamic acid (Gla) residues. The
double carboxy group on Gla residues has high affinity for the binding
of calcium. Bone formation involves vitamin K-dependent small peptide
osteocalcin (bone-Gla-protein) that is secreted by osteoblasts.
Serum concentrations of vitamin K1 reflect in part the capacity of the serum to carry the vitamin. Vitamin K1 is a lipid, and little is known about the binding of this vitamin to proteins other than that it is transported in serum by the lipoproteins. It is not known whether there is a specific "vitamin K1-binding protein" in tissues as has been suggested for vitamin E as a "tocopherol-binding protein" (1).
Deficiency of vitamin K will lead to defective -carboxylation of
vitamin K-dependent proteins and will be manifested by the failure of
these proteins to function normally (2)(3)(4)(5)(6)(7)(8). Low serum
concentrations of vitamin K1 have been reported
to occur in patients with traumatic bone fractures (4)(5)(6),
although others have reported nonsignificant decreases in vitamin
K1 in the immediate 48 h after low-energy
trauma hip fracture (9). These serum concentrations were
considered pathological because they were significantly lower than
values in age-matched control subjects. Recent studies, however, have
shown that even very low absolute concentrations of vitamin
K1 in serum do not reflect the vitamin K status
(3)(10)(11). The use of a relative
measure of serum vitamin K1, the ratio of vitamin
K1 to lipids (11) or to
apolipoproteins (3)(12), has become essential in
evaluating vitamin K1 nutritional status as has
been shown for vitamin E (11). Under routine
conditions, the ratios of vitamin K1 and vitamin
E to other plasma lipoproteins components are relatively constant.
Changes in the metabolism of lipoproteins such as are the case with
hypercholesterolemia do not seem to affect such ratios
(3)(11).
Stepwise linear regression methods have determined that serum concentrations of vitamin K1 could best be predicted by using equations excluding lipids but containing only apolipoprotein A1 and B concentrations: Vitamin K1 (µg/L) = 369 x apolipoprotein B (g/L) x apolipoprotein A1 (g/L). The correlation coefficient between the calculated values of vitamin K1 using serum concentrations of apolipoproteins A1 and B and the measured (HPLC) values of vitamin K1 was 0.83 (3).
It has been suggested that the low serum concentrations of vitamin K1 observed in patients with traumatic bone fractures was a consequence of sequestration of this vitamin from the circulation for use at the fracture site where it is required for the Gla transformation of special bone peptides (4).
LDL, which contains apolipoprotein B, is a negative acute phase reactant and is induced by inflammation (13)(14) such as with traumatic bone fractures. A decrease in synthesis and an increase in degradation of apolipoprotein B have been shown to occur. The reduction in apolipoprotein B concentration is reflected by a reduction in serum LDL concentrations as has been shown after acute myocardial infarction (13)(14). Consequently, because of the relationship of vitamin K1 and apolipoprotein B (3), this may reflect the reduction in serum vitamin K1 concentrations observed in patients soon after fracture. Thus it is possible that the lower concentration of vitamin K1 in serum observed after bone fracture is attributable to a generalized lipoprotein carrier phenomenon (the negative acute phase response of LDL), which is an alternative explanation to the sequestration of vitamin K1 from its carrier to bone fracture site.
To test whether the metabolism of vitamin K1 in patients with bone fractures is altered independently of the lipoprotein carrier system, we measured vitamin K1 (15) and apolipoproteins A1 and B (3)(16) in sera from eight patients admitted for treatment of traumatic bone fractures in the pelvis. The sera were collected from all male patients (mean age, 45.0 years; range, 15–64 years) within 10 days (range, 1–9 days) of sustaining the fracture (4). The exclusion criteria were blood transfusions or surgical procedures before the period of sample collection and past and present illnesses related to bone metabolism. No subjects had been treated for osteoporosis, and none received medications before or during the study that might have affected calcium metabolism.
Serum samples were also taken from 12 healthy male subjects (mean age, 46.4 years; range, 19–55 years) for analyses of vitamin K1, apolipoprotein A1, and apolipoprotein B. There was no statistical difference (Student t-test) between the ages of controls and patients with fractures. Informed consent was obtained from all participants. The procedures used for these human studies were in accord with the Helsinki Declaration of 1975, as revised in 1996.
Serum vitamin K1 concentrations from all subjects were also calculated by applying derived equations containing apolipoproteins A1 and B concentrations (3).
The mean serum concentration of vitamin K1
was significantly lower in the fracture patients than in the control
subjects, but the concentrations of apolipoproteins
A1 and B were not significantly different in the
two groups (Table 1
).
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When vitamin K1 concentrations in serum were
calculated by the equation: Vitamin K1
(µg/L) = 369 x apolipoprotein B (g/L) x
apolipoprotein A1 (g/L) (3), the
obtained mean value for the control subjects was 348 µg/L, similar to
the value of 361 µg/L (Table 1
). The ratio of corresponding
individual measured/calculated values of vitamin
K1 in serum was 1.04 (SD = 0.04).
In contrast, the calculated mean concentration of vitamin
K1 from the bone fracture patients, 369 µg/L,
was significantly different (P <0.01) from the measured
mean concentration of 221 µg/L (Table 1
). The ratio of corresponding
individual measured/calculated values of vitamin
K1 in serum of bone fracture patients was 0.60
(SD = 0.13). This ratio was significantly different (P
<0.001) from that of the control subjects (Table 1
).
The current results confirm that the circulating serum vitamin K1 concentrations are reduced shortly (within 10 days) after bone fracture (4)(5)(6)(7). It is known that vitamin K1 deficiency occurs in elderly subjects (6). However, in our study, because all the subjects were males and their ages were not relatively old, together with the fact that the age range of the controls was similar to that of the patients, it is unlikely that age had an effect on our observations. In control subjects, vitamin K1 concentrations in serum can be calculated from the concentrations of apolipoproteins A1 and B (3). However, in patients after bone fracture, the changes in serum vitamin K1 concentrations are not paralleled with changes in their carrier systems, the lipoproteins. There is no evidence that after bone fracture apolipoprotein A1 and B concentrations in serum are altered. It appears that serum vitamin K1 is utilized independent of its lipoprotein carriers in serum. These observations support the concept that this vitamin is sequestered from lipoproteins in the circulation for use, perhaps at the fracture site (4). The current results indicate that the mode of sequestration of vitamin K1 is independent of the metabolism of lipoproteins, an observation that has not previously been reported. In patients without bone fractures, the vitamin K1 concentration can be predicted from the concentrations of apolipoproteins A1 and B, whereas it cannot be predicted by the same equation in patients with bone fractures. The mechanism of vitamin K1 delivery to the fracture site remains to be elucidated, but it could conceivably operate via a putative receptor in which the vitamin K1 is selectively taken up, analogous to the interaction of HDL with cells without the loss of its apolipoprotein components. This study further indicates a need to validate the use of equations containing the serum concentrations of apolipoproteins A1 and B to calculate vitamin K1 concentrations in serum (3) in patient groups where changes in vitamin K1 metabolism are in question.
Acknowledgments
This work was supported by grants from Curacel International Pty Ltd and the National Health and Medical Research Council of Australia. We thank Peter Roeser for supplying the serum from the patients. We gratefully acknowledge technical assistance from Karim Cham, Tania Chase, Annette Miles, Mark Jones, and Kelly Kingston.
References
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