Concepts and Controversies in Evaluating Vitamin K Status in Population-Based Studies (Shea MK and Booth SL)

As new roles for vitamin K in health and disease emerge, so has interest in measuring vitamin K status in population-based studies. To that end, a review just published in Nutrients evaluated the methods currently available to assess vitamin K status in human studies.

Vitamin K nutritional status is primarily accomplished using dietary questionnaires and/or biomarkers. Because food composition databases in the United States are most complete for phylloquinone (vitamin K1, the primary form in Western diets), emphasis has been on phylloquinone intakes and associations with chronic diseases. Yet there is growing interest in menaquinone (vitamin K2) intakes for which the food composition databases need to be expanded.

According to the review, phylloquinone is commonly measured in circulation, has robust quality control schemes and changes in response to phylloquinone intake. Conversely, menaquinones are generally not detected in circulation unless large quantities are consumed. The undercarboxylated (inactive) fractions of three vitamin K-dependent proteins are measurable in circulation, change in response to vitamin K supplementation and are modestly correlated. Since different vitamin K-dependent proteins are implicated in different diseases, the appropriate vitamin K-dependent protein biomarker depends on the outcome under study. In contrast to other nutrients, there is no single biomarker that is considered a gold-standard measure of vitamin K status.

The researchers note the following as options to evaluate vitamin K status, and specifically Vitamin K2:

  • Dietary intake assessment by food frequency questionnaire (FFQ ). Dietary intake assessment by FFQ is convenient and easily implemented. Currently, food composition databases are being expanded to include multiple menaquinone forms, so dietary questionnaires will no longer be limited to phylloquinone intake. However, the content of K2 can be different even in the same type of food products; the cheese gouda can contain either no Vitamin K2 or a decent amount of K2 (dependent on the production). Additionally, the FFQ is subjective and relies on individuals’ recall ability and perceptions, which can bias the estimates of nutrient intake.
  • The use of biomarkers to estimate vitamin K status, such as circulating vitamin K or noncarboxylated or carboxylated vitamin-K dependent proteins (VKDP). The most popular VKDP as a status of vitamin K are undercarboxylated prothrombin (PIVKA-II), undercarboxylated fraction of osteocalcin (ucOC), and dephosphorylated undercarboxylated form (dp)ucMGP. Of the three, ucOC reflects vitamin K intake more so than PIVKA-II and is thought to be a more sensitive indicator of vitamin K status in community-based individuals. Further, during dietary vitamin K depletion, the ucOC increases whereas it decreases in response to vitamin K supplementation.

Moreover, the different measures of vitamin K status are influenced by physiological factors in addition to vitamin K. For example, the amount of undercarboxylated vitamin K-dependent proteins in circulation depends on the total amount of protein, in addition to vitamin K availability. If these measures are not corrected for the total amount of the protein under study, they may reflect total protein status as well as vitamin K status, which can confound the interpretation of the results, according to the researchers.

“The assessment of vitamin K nutritional status in population and clinical studies is important to better understanding of vitamin K’s role in health and disease. However, there is no single biomarker that is considered a gold-standard measure of vitamin K status,” says Dr. Katarzyna Maresz, president of the International Science and Health Foundation. “While even the alternatives offered by the researchers have their drawbacks, there is potential, and this review has helped to highlight the urgency of establishing that gold-standard measure for Vitamin K2.”


Shea MK and Booth SL. Concepts and Controversies in Evaluating Vitamin K Status in Population-Based Studies. Nutrients 2016, 8(1); doi:10.3390/nu8010008.


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