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Community child health, public health, and epidemiology
Vitamin K supplementation in cystic fibrosis
  1. J H L van Hoorn1,
  2. J J E Hendriks1,
  3. C Vermeer2,
  4. P Ph Forget1
  1. 1Department of Paediatrics, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, Netherlands
  2. 2Department of Biochemistry, Maastricht University, PO Box 616, 6200 MD Maastricht, Netherlands
  1. Correspondence to:
    Dr J J E Hendriks
    Department of Paediatrics, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, Netherlands; jhepaed.azm.nl

Abstract

The relation between different doses of vitamin K supplementation, several bone markers, and PIVKA-II concentrations in cystic fibrosis (CF) patients compared to controls was evaluated. Results suggest that a increased vitamin K intake may have significant health benefits for children with CF.

  • cystic fibrosis
  • vitamin K
  • osteocalcin
  • PIVKA-II
  • bone status

https://doi.org/10.1136/adc.88.11.974

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    Cystic fibrosis (CF) is the most prevalent fatal, autosomal, recessive genetic disease in white people, affecting approximately 1 in 3400 live births.

    Children with CF are at high risk for developing vitamin K deficiency because of fat malabsorption. The prevalence of vitamin K deficiency in CF is not precisely known, but it is common in unsupplemented patients with pancreatic insufficiency.1

    Besides its function in blood clotting, accumulating evidence suggests that vitamin K plays a key role in improving bone health.1 Vitamin K is a cofactor in the post-translational γ-carboxylation of glutamic acid residues (Glu) to form γ-carboxyglutamic acid (Gla) residues which are able to bind calcium. Gla containing proteins are found in the clotting cascade (vitamin K dependent clotting factors) and in bone (osteocalcin). In the absence of vitamin K, Glu residues remain undercarboxylated, resulting in a strongly decreased affinity for calcium. Undercarboxylated coagulation factors are known as PIVKAs (protein induced by vitamin K absence); notably PIVKA-II (undercarboxylated prothrombin) serves as a sensitive marker for vitamin K status. Circulating undercarboxylated osteocalcin (u-OC) is considered to be an even more sensitive marker for vitamin K status than PIVKA-II concentrations.1 High serum u-OC concentrations are indicative of a poor bone status and are associated with low bone mineral density and increased risk of osteoporotic fractures.2,4

    There is little consensus about the appropriate dose needed to prevent vitamin K deficiency in CF. Even in a large CF database (Dundee, UK) no indication can be found concerning the most appropriate dose of vitamin K to be used. Because vitamin K deficiency in CF patients may affect bone mineral status, associated complications may be prevented by adequate vitamin K supplementation.

    SUBJECTS AND METHODS

    In this uncontrolled study, 39 subjects were divided in four groups: 19 healthy subjects, 10 CF patients with no vitamin K (CFno), six CF patients with low dose vitamin K (<0.25 mg/day  =  CFlow), and four CF patients with high dose vitamin K (⩾1 mg/day  =  CFhigh) supplementation. Inclusion criteria for CF patients were pancreas insufficiency without liver function disturbances. Serum or urine concentrations of different bone markers and serum PIVKA-II concentrations were determined in healthy subjects and in and CF patients on different vitamin K supplementation. Serum concentrations of the bone formation markers osteocalcin (OC, total OC (t-OC), undercarboxylated OC (u-OC) and carboxylated OC (c-OC)) and bone alkaline phosphatase (BAP) as well as the bone resorption marker N-terminal collagen type 1 (NTX) were determined. The bone resorption marker deoxypyrodinoline (DPD) was determined in urine.

    Data were analysed using the non-parametric Wilcoxon’s (Mann-Whitney) rank sum test (p<0.05 two sided).

    RESULTS

    Serum t-OC was measured in 10 controls only and was significantly higher in CFhigh patients (p = 0.016) than in controls (see fig 1). Serum u-OC was significantly lower in CFhigh patients than in controls (p = 0.005), CFno (p = 0.011), and CFlow patients (p = 0.033). Serum c-OC was significantly lower in CFno (p = 0.001) and CFlow patients (p = 0.011) than in controls, whereas c-OC was significantly higher in CFhigh patients than in CFno (p = 0.005) and CFlow patients (p = 0.010).

    Figure 1
    Figure 1

    Boxplot showing total osteocalcin (t-OC in black), undercarboxylated osteocalcin (u-OC in grey), and carboxylated osteocalcin (c-OC in white) for vitamin K supplementation in CF patients, compared to healthy controls. Vitamin K supplementation is shown in three different groups: CFno  =  no supplementation; CFlow  =  <0.25 mg/day; and CFhigh  =  ⩾1 mg/day. Significant p values are shown.

    There was no significant difference in serum BAP and urinary DPD between the four groups. Serum NTX was significantly lower in CFno (p = 0.017) and CFlow patients (p = 0.020) than in controls. Serum PIVKA-II concentrations were significantly higher in CFno (p = 0.012) and CFlow patients (p = 0.022) than in controls (see fig 2).

    Figure 2
    Figure 2

    Boxplot showing PIVKA-II concentrations in CF patients with three different doses of vitamin K supplementation, compared to healthy controls. Significant p values are shown.

    DISCUSSION

    High u-OC, low c-OC and raised PIVKA-II concentrations in all but CFhigh patients suggest a vitamin K dependent carboxylation defect in CF patients. In our study only CFhigh patients showed normal PIVKA-II concentrations suggesting that all other groups were vitamin K deficient to some degree. Hence only patients receiving a high dose (⩾1 mg/day) of vitamin K had an adequate vitamin K status. Several studies showed that vitamin K supplementation induced a decrease of serum u-OC and may alter other bone markers such as NTX and BAP.5–7 Our data showed a similar tendency, with the most prominent changes in the vitamin K-dependent osteocalcin. Whether the improved vitamin K status in CFhigh patients is associated with improved bone health still remains unclear. If vitamin K supplementation resulted in increased bone formation, both bone formation markers t-OC and BAP would be expected to be high in the CFhigh group, whereas this was only found to be the case for t-OC. Similarly, low bone resorption could be regarded as a beneficial effect. Again, our data are inconsistent, because NTX was significantly lower in the CFhigh group, whereas DPD was not. In conclusion, our results suggest that a high dose (⩾1 mg/day) vitamin K supplementation is needed to improve the vitamin K status of children with CF and to prevent potential vitamin K deficiency related complications. Long term (more than one year) randomised follow up studies are required to clarify the relation between vitamin K status and bone health in CF. This aspect will be of increasing importance as CF patients grow older and have a higher frequency of pathological fractures.2,4

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