The Effects of Parenteral K1 Administration in Pseudoxanthoma Elasticum Patients Versus Controls. A Pilot Study

Abstract

IntroductionPseudoxanthoma elasticum (PXE) is a rare disease caused by mutations in the ABCC6 gene. Vitamin K1 is involved in the posttranslational carboxylation of some proteins related to inhibition of the calcification process. Our aim was to investigate, in patients affected by PXE, baseline levels of vitamin K1-dependent proteins and -metabolites and whether parenteral administration of phytomenadione was effective in modulating their levels.MethodsWe included eight PXE patients with typical clinical symptoms (skin, retina, and vascular calcification) and two ABCC6 causative mutations; 13 clinically unaffected first-degree patients’ relatives (9 carrying one ABCC6 mutation and 4 non-carriers). We assessed urinary vitamin K1 metabolites and serum Glu- and Gla-OC, Gas6 and undercaboxylated prothrombin (PIVKA-II), at baseline and after 1 and 6 weeks after a single intramuscular injection of 10 mg vitamin K1.ResultsComparison of PXE patients, heterozygous, and non-carriers revealed differences in baseline levels of serum MK-4 and of urinary vitamin K metabolites. The response to phytomenadione administration on vitamin K-dependent proteins was similar in all groups.ConclusionThe physiological axis between vitamin K1 and vitamin K-dependent proteins is preserved; however, differences in the concentration of vitamin K metabolites and of MK-4 suggest that vitamin K1 metabolism/catabolism could be altered in PXE patients.

The Role of Vitamin K and Its Related Compounds in Mendelian and Acquired Ectopic Mineralization Disorders

“…Increased serum levels of carboxylated OC after vitamin K administration in PXE patients was also noted, suggesting preserved vitamin K-dependent γ-glutamyl carboxylation. Similar serum levels of PIVKA-II (protein induced by vitamin K absence or antagonist-II, uncarboxylated prothrombin) were measured in PXE patients compared to controls, confirming that the vitamin K-dependent coagulation factors are not affected in PXE, contrary to PXE-like syndrome (see below) [55].…”

“…Finally, Carrillo-Linares et al [55] very recently studied the effect of parenteral administration of a single dose of vitamin K1 in PXE patients versus controls, measuring baseline and 1 and 6 weeks post injection vitamin K levels, urinary concentration of vitamin K metabolites, and serum concentration of carboxylated OC. Higher serum MK-4 levels at baseline were detected in PXE patients compared to controls, with a significant increase in MK-4 concentration at 1 and 6 weeks post-vitamin K injection, indicating that the conversion of vitamin K1 to vitamin K2 (MK-4) is conserved in PXE patients [55]. Urinary vitamin K metabolites were found to be lower in PXE patients at baseline compared to controls, a difference which was maintained after vitamin K administration [55].…”

“…Higher serum MK-4 levels at baseline were detected in PXE patients compared to controls, with a significant increase in MK-4 concentration at 1 and 6 weeks post-vitamin K injection, indicating that the conversion of vitamin K1 to vitamin K2 (MK-4) is conserved in PXE patients [55]. Urinary vitamin K metabolites were found to be lower in PXE patients at baseline compared to controls, a difference which was maintained after vitamin K administration [55]. Increased serum levels of carboxylated OC after vitamin K administration in PXE patients was also noted, suggesting preserved vitamin K-dependent γ-glutamyl carboxylation.…”

From membrane to mineralization: the curious case of the ABCC6 transporter

“…Of interest is that the data of Brampton et al show that vitamin K serum levels in PXE mice increase much less than in wild-type littermates after supplementation, suggesting that ABCC6 deficiency is (indirectly) related to a less-efficient vitamin K absorption, possibly explaining the low vitamin K levels in patients [37]. Such an altered vitamin K metabolism was recently also noted by Carrillo-Linares et al [40]. Though not suitable as a monotherapy for ABCC6 deficiency, vitamin K may still hold promise as part of a combined drug treatment.…”

“…Over the years, ABCC6 has been suggested to have different functions, sometimes depending on the tissue it is expressed in, which is not uncommon for ABC transporters in general [33,34]. It was hypothesized that ABCC6 might increase oxidative stress resistance for the local extracellular matrix, be involved in auto-/ paracrine hepatic signaling or-following the demonstration of low vitamin K serum levels in PXE patients -that it might transport vitamin K [35][36][37][38][39][40]. However, these hypotheses were either revoked-as is the case for, for example, glutathione-conjugated vitamin K transport-or there are currently no data available that directly confirm such a role for ABCC6 [39].…”