by Aliza Becker, BA, MPS
Vitamin K is the generic name for a family of fat-soluble compounds that share a common 2-methyl-1,4-naphthoquinone ring structure. Vitamin K is naturally present in some foods or available as a dietary supplement.1 Its existence was first reported in the 1930s by Danish biochemist Henrik Dam, who observed that chicks fed a low-fat diet free from sterols as part of research on cholesterol metabolism tended to develop subcutaneous and intramuscular hemorrhages;2 subsequent research led to the discovery of an “anti-hemorrhagic factor” designated as vitamin K (with the “K” standing in for the German word koagulationsvitamin).3 Dam was later awarded the Nobel Prize in Physiology or Medicine in 1943, sharing with Edward Adelbert Doisy, an American biochemist, for their discovery of vitamin K and its chemical structure, respectively.4
Sources and Dosing
Two forms of vitamin K exist in the United States (US) food supply.1 Vitamin K1 (phylloquinone [PK]) is found in green, leafy vegetables, such as collards, spinach, and broccoli, as well as in soybean oil and canola oil.5 In contrast, vitamin K2 (menaquinone [MK]) is found variably in certain animal-based foods and is mainly produced by bacteria and archaea. Notably, at least 15 types of MKs exist that are distinguishable by the number of isoprene units in their side chains. In a study of the US diet, Elder et al6 reported that chicken, cheddar cheese, and egg yolks contained the highest amounts of MK-4, while Fu et al,7 following a similar analysis of the US food supply, found that all processed pork products and fresh pork cuts contained MK-4, MK-10, and MK-11. Vermeer et al8 reported that many cheeses contain MK-4 through MK-9, with levels depending on factors such as fat content, age, and country of origin. Meanwhile, among the vegetables they assessed, only the two fermented ones, natto and sauerkraut, contained MK8; the latter, a Japanese dish made from fermented soybeans, is considered a good source of MK-7.9 Certain gut bacteria, such as Escherichia coli (E. coli) and Bacteroides species, may also produce MK.10
According to US dietary guidelines, the recommended daily amount of vitamin K for adults over the age of 19 years is 90μg/day for women (including pregnant or breastfeeding women) and 120μg/day for men.11 Children require anywhere from 2 to 75μg/day, depending on their age.11
Although the U.S. population largely meets the recommended daily intake for vitamin K, certain populations are at risk for deficiency. Newborns are typically given oral and/or intramuscular prophylactic vitamin K after birth to prevent hemorrhagic disease of the newborn,12,13 which can occur soon after birth due to the limited placental transfer of this vitamin during gestation and their sterile gut or later in infancy when coupled with insufficient vitamin K in breast milk.14 Although some research has previously suggested a link between intramuscular vitamin K and childhood leukemia,15 later reports have since argued against this connection.16 Individuals with disorders characterized by the malabsorption of fat, such as cystic fibrosis, chronic pancreatitis, and inflammatory bowel diseases, as well as those who have undergone certain surgical procedures, such as total pancreatectomy, small-bowel resections, or bariatric surgical procedures, may also benefit from vitamin K supplementation.17 Patients on hemodialysis may also present with a poor vitamin K status,18 and individuals taking drugs that interfere with vitamin K metabolism are similarly at risk of deficiency.19
Effects in the Body
For several decades after its discovery, vitamin K was thought to be used only for the synthesis of four blood-coagulation factors in the liver. In more recent years, however, researchers have expanded their focus, elucidating possible roles of vitamin K in the transportation of calcium to bone and the reduction of vascular calcification via the carboxylation of osteocalcin and activation of matrix Gla protein, two vitamin K–dependent proteins (VKDPs), respectively.
Effects on bone health. Sim et al20 reported that increased dietary intake of PK-rich green leafy vegetables for four weeks in a population of middle-aged healthy men and women led to improved osteoblast function, which is thought to be due to vitamin K’s role in increasing osteocalcin entry into the bone matrix and improving the material properties of bone (e.g., toughness). Moore et al21 found that the serum PK concentration was significantly lower in their study group of postmenopausal women with prior fractures compared to the no-fracture group and was independently associated with fracture risk. Cheung et al22 also suggested that daily PK supplementation may protect against fractures in postmenopausal women with osteopenia. Torbergsen et al23 also observed that low serum concentrations of PK and 25-hydroxyvitamin D were significantly associated with risk of fracture in elderly patients hospitalized for hip fracture, implicating a synergistic effect between these two vitamins in addition to their independent roles.
Effects on cardiovascular health. Beulens et al24 reported that high dietary MK intake, but probably not PK, may limit coronary calcification. Geleijnse et al25 reported that MK intake was inversely related to all-cause mortality and severe aortic calcification, while PK intake did not correlate with any of their study outcomes. Vissers et al26 noted that a high intake of MKs was associated with a reduced risk of peripheral arterial disease, at least in participants with hypertension, but a high intake of PK was not associated with the same. Gast et al27 suggested that a high intake of MKs, especially MK-7, MK-8, and MK-9, could protect against coronary heart disease. However, PK may not be without its benefits: Shea et al28 reported that PK supplementation slowed the progression of coronary artery calcification in healthy older adults with pre-existing coronary artery calcification. In patients with blood-clotting disorders, vitamin K antagonists (e.g., warfarin) are used to prevent stroke in patients with atrial fibrillation as well as venous thromboembolism, while PK itself is given to reduce the anticoagulant effects of such drugs.29 Of note, vitamin K antagonists have been linked to higher levels of coronary artery and vascular calcification,30,31 but the coronary-calcification effect appears absent with the use of newer non–vitamin K antagonist oral anticoagulants.31
Other effects on health. Vitamin K may also lower the risk of type 2 diabetes mellitus,32 and research is ongoing concerning its potential in the treatment of cancer, particularly with regard to the effects of MKs on cell-cycle arrest and the inhibition of cell differentiation, apoptosis, autophagy, and invasion.33 More generally, vitamin K may act as an anti-inflammatory34 and an antioxidant,35 and it has been associated with the inhibition of cognitive decline36 and the prevention and treatment of neurodegenerative diseases, such as Alzheimer’s.37
Most recently, research has reported that levels of dephosphorylated-uncarboxylated matrix Gla protein, a marker of vitamin K deficiency,38 was greater in patients with COVID-19 relative to healthy controls,39 with higher levels present in those with more severe disease.40
Editor’s note: Vitamin K can lessen the effectiveness of Warfarin, a commonly prescribed blood thinner. Consult with your doctor to determine which vitamin K regimen is best for you.
About the Author
Ms. Becker is the managing editor of The Journal of Innovations in Cardiac Rhythm Management. She also works as a freelance editor and as a teaching assistant for the George Washington University’s Master of Professional Studies in Publishing program.
Sources
1. Booth SL. Vitamin K: food composition and dietary intakes. Food Nutr Res. 2012;56.
2. Dam H. Cholesterol metabolism in hen eggs and chickens [in German]. Niochem Z. 1929;215:475–492.
3. Dam H. The antihaemorrhagic vitamin of the chick. Biochem J. 1935;29(6):1273–1285.
4. Raju TN. The Nobel chronicles. 1943: Henrik Carl Peter Dam (1895–1976); and Edward Adelbert Doisy (1893–1986). Lancet. 1999;353(9154):761.
5. Booth SL. Vitamin K: food composition and dietary intakes. Food Nutr Res. 2012;56:10.3402/fnr.v56i0.5505.
6. Elder SJ, Haytowitz DB, Howe J, et al. Vitamin k contents of meat, dairy, and fast food in the U.S. diet. J Agric Food Chem. 2006;54(2):463–467.
7. Fu X, Shen X, Finnan EG, et al. Measurement of multiple vitamin K forms in processed and fresh-cut pork products in the U.S. food supply. J Agric Food Chem. 2016;64(22):
4531–4535.
8. Vermeer C, Raes J, van ’t Hoofd C, et al. Menaquinone content of cheese. Nutrients. 2018;10(4):446.
9. Tsukamoto Y, Ichise H, Kakuda H, Yamaguchi M. Intake of fermented soybean (natto) increases circulating vitamin K2 (menaquinone-7) and gamma-carboxylated osteocalcin concentration in normal individuals. J Bone Miner Metab. 2000;18(4):216–222.
10. Ramotar K, Conly JM, Chubb H, Louie TJ. Production of menaquinones by intestinal anaerobes. J Infect Dis. 1984;150(2):213–218.
11. National Institutes of Health Office of Dietary Supplements. Vitamin K fact sheet for consumers. Available at: https://ods.od.nih.gov/factsheets/VitaminK-Consumer/. Accessed October 21, 2021.
12. American Academy of Pediatrics, Committee on Nutrition Vitamin K compounds and the water-soluble analogues: use in therapy and prophylaxis in pediatrics. Pediatrics. 1961;28:501–507.
13. American Academy of Pediatrics Committee on Fetus and Newborn. Controversies concerning vitamin K and the newborn. American Academy of Pediatrics Committee on Fetus and Newborn. Pediatrics. 2003;112(1 Pt 1):191–192.
14. Kher P, Verma RP. Hemorrhagic disease of newborn. [Updated 2021 Jul 3]. In: StatPearls [Internet]. Treasure Island, Florida: StatPearls Publishing; 2021.
15. Golding J, Greenwood R, Birmingham K, Mott M. Childhood cancer, intramuscular vitamin K, and pethidine given during labour. BMJ. 1992;305(6849):341–346.
16. Fear NT, Roman E, Ansell P, et al. Vitamin K and childhood cancer: a report from the United Kingdom Childhood Cancer Study. Br J Cancer. 2003;89(7):1228–1231.
17. Siener R, Maxhaka I, Alteheld B, et al. Effect of fat-soluble vitamins A, D, E and K on vitamin status and metabolic profile in patients with fat malabsorption with and without urolithiasis. Nutrients. 2020;12(10):3110.
18. Cranenburg ECM, Schurgers LJ, Uiterwijk HH, et al. Vitamin K intake and status are low in hemodialysis patients. Kidney Int. 2012;82(5):605–610.
19. Tufano A, Coppola A, Contaldi P, et al. Oral anticoagulant drugs and the risk of osteoporosis: new anticoagulants better than old? Semin Thromb Hemost. 2015;41(4):382–388.
20. Sim M, Lewis JR, Prince RL, et al. The effects of vitamin K-rich green leafy vegetables on bone metabolism: a 4-week randomised controlled trial in middle-aged and older individuals. Bone Rep. 2020;12:100274.
21. Moore AE, Kim E, Dulnoan D, et al. Serum vitamin K 1 (phylloquinone) is associated with fracture risk and hip strength in post-menopausal osteoporosis: a cross-sectional study. Bone. 2020;141:115630.
22. Cheung AM, Tile L, Lee Y, et al. Vitamin K supplementation in postmenopausal women with osteopenia (ECKO trial): a randomized controlled trial. PLoS Med. 2008;5(10):e196.
23. Torbergsen AC, Watne LO, Wyller TB, et al. Vitamin K1 and 25(OH)D are independently and synergistically associated with a risk for hip fracture in an elderly population: a case control study. Clin Nutr. 2015;34(1):101–106.
24. Beulens JWJ, Bots ML, Atsma F, et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2009;203(2):489–493.
25. Geleijnse JM, Vermeer C, Grobbee DE, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. 2004;134(11):
3100–3105.
26. Vissers LET, Dalmeijer GW, Boer JMA, et al. The relationship between vitamin K and peripheral arterial disease. Atherosclerosis. 2016;252:15–20.
27. Gast GCM, de Roos NM, Sluijs I, et al. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis. 2009;19(7):504–510.
28. Shea MK, O’Donnell J, Hoffmann U, et al. Vitamin K supplementation and progression of coronary artery calcium in older men and women1,2,3,4. Am J Clin Nutr. 2009;89(6):1799–1807.
29. Zirlik A, Bode C. Vitamin K antagonists: relative strengths and weaknesses vs. direct oral anticoagulants for stroke prevention in patients with atrial fibrillation. J Thromb Thrombolysis. 2017;43(3):
365–379.
30. Koos R, Mahnken AH, Mühlenbruch G, et al. Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography. Am J Cardiol. 2005;96(6):747–749.
31. Weijs B, Blaauw Y, Rennenber JMW, et al. Patients using vitamin K antagonists show increased levels of coronary calcification: an observational study in low-risk atrial fibrillation patients. Eur Heart J. 2011;32(20):2555–2562.
32. Manna P, Kalita J, et al. Beneficial role of vitamin K supplementation on insulin sensitivity, glucose metabolism, and the reduced risk of type 2 diabetes: a review. Nutrition. 2016;32(7–8):732–739.
33. Xv F, Chen J, Duan L, Li S. Research progress on the anticancer effects of vitamin K2. Oncol Lett. 2018;15(6):
8926–8934.
34. Fujii S, Shimizu A, Takeda N, et al. Systematic synthesis and anti-inflammatory activity of ω-carboxylated menaquinone derivatives—investigations on identified and putative vitamin K metabolites. Bioorg Med Chem. 2015;23(10):2344–2352.
35. Li J, Wang H, Rosenberg PA. Vitamin K prevents oxidative cell death by inhibiting activation of 12-lipoxygenase in developing oligodendrocytes. J Neurosci Res. 2009;87(9):1997–2005.
36. Alisi L, Cao R, De Angelis C, et al. The relationships between vitamin K and cognition: a review of current evidence. Front Neurol. 2019;10:239.
37. Popescu A, German M. Vitamin K2 holds promise for Alzheimer’s prevention and treatment. Nutrients. 2021;13(7):2206.
38. Dalmeijer GW, van der Schouw YT, Magdeleyns E, et al. The effect of menaquinone-7 supplementation on circulating species of matrix Gla protein. Atherosclerosis. 2012;225(2):
397–402.
39. Desai AP, Dirajlal-Fargo S, Durieux JC. Vitamin K & D deficiencies are independently associated with COVID-19 disease severity. Open Forum Infect Dis. 2021;8(10):ofab408.
40. Dofferhoff ASM, Piscaer I, Schurgers LJ, et al. Reduced vitamin K status as a potentially modifiable risk factor of severe COVID-19 [published online ahead of print August 27, 2020]. Clin Infect Dis.
