The Multifaceted Roles of Vitamin K: A Comprehensive Review of its Chemical Forms, Physiological Functions, and Health Implications

Many thanks to our sponsor Esdebe who helped us prepare this research report.

Abstract

Vitamin K, a class of fat-soluble naphthoquinones, stands as an indispensable micronutrient with roles extending far beyond its initial recognition as a coagulant. This comprehensive review delves into the intricate world of vitamin K, dissecting its primary forms: phylloquinone (vitamin K₁) and the diverse family of menaquinones (vitamin K₂). We explore their distinct chemical structures, diverse dietary origins, sophisticated absorption and metabolic pathways, and the compelling historical narrative that led to their discovery. By synthesizing a vast body of contemporary research, this report aims to furnish an in-depth, nuanced understanding of vitamin K’s critical involvement in pivotal physiological processes, including hemostasis, bone integrity, and cardiovascular health, while also touching upon its emerging roles in neurological function and cellular proliferation. The evolving understanding of the specific biological activities of K₁ versus the various K₂ forms underscores the imperative for a more granular approach to dietary recommendations and therapeutic applications.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

Vitamin K, derived from the German word ‘Koagulation-vitamin’, is a fundamental fat-soluble micronutrient whose physiological significance has continually expanded since its initial discovery. Encompassing a group of structurally related lipophilic vitamins, vitamin K plays a central role as a cofactor for the enzyme γ-glutamyl carboxylase (GGCX), which is crucial for the post-translational modification of a specific set of proteins known as vitamin K-dependent proteins (VKDPs) [1]. This modification, involving the carboxylation of glutamic acid residues to γ-carboxyglutamic acid (Gla), enables these proteins to bind calcium ions, thereby activating their biological functions. While historically celebrated for its pivotal role in blood coagulation, modern research has unequivocally broadened our understanding of vitamin K’s influence across numerous biological systems, including bone metabolism, cardiovascular health, and potentially neurological function and cellular growth regulation [2, 3].

The vitamin K family primarily comprises two natural forms: phylloquinone (vitamin K₁), predominantly found in green leafy plants, and menaquinones (vitamin K₂), a series of compounds with varying isoprenoid side chains, primarily produced by bacteria and found in fermented foods and some animal products. Although sharing a common mechanism of action through the γ-carboxylation cycle, these vitamers exhibit distinct absorption efficiencies, tissue distribution patterns, and ultimately, exert differential physiological effects, challenging the traditional view of vitamin K as a monolithic entity [4].

This detailed report will systematically explore the chemical distinctions, diverse dietary landscape, and complex metabolic journey of vitamin K. Furthermore, it will meticulously examine its multifaceted roles in human physiology, elucidate the implications of deficiency and subclinical insufficiency, and discuss current dietary recommendations alongside future research trajectories. By delving into the scientific intricacies of this remarkable micronutrient, we aim to provide a holistic and updated perspective on its profound significance for optimal human health.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Chemical Forms and Physiological Functions of Vitamin K

The term vitamin K represents a collective of naphthoquinone derivatives that share a common 2-methyl-1,4-naphthoquinone ring structure but differ in the side chain at position 3. These structural variations dictate their sources, bioavailability, tissue distribution, and specific physiological roles. Understanding these distinctions is paramount for appreciating the vitamin’s diverse impact on health.

2.1 Phylloquinone (Vitamin K₁)

Phylloquinone, designated as vitamin K₁, is characterized by a phytyl side chain, a fully saturated isoprenoid chain of four units. This form is exclusively synthesized by plants and is the predominant dietary vitamin K consumed in Western diets. It is an integral component of the photosynthetic machinery, specifically within photosystem I, where it acts as an electron acceptor [5].

2.1.1 Role in Blood Coagulation

Vitamin K₁’s most well-established function is its crucial role in hemostasis, the process by which blood clots are formed to prevent excessive bleeding. It serves as a vital cofactor for the microsomal enzyme γ-glutamyl carboxylase (GGCX), which catalyzes the post-translational carboxylation of specific glutamic acid (Glu) residues to γ-carboxyglutamic acid (Gla) residues in precursor proteins. This modification occurs in the liver, primarily, and is essential for the activation of several key coagulation factors: Factor II (prothrombin), Factor VII, Factor IX, and Factor X, as well as the anticoagulant proteins Protein C, Protein S, and Protein Z [6].

The Gla residues enable these proteins to bind calcium ions, which is a prerequisite for their conformational change and subsequent interaction with phospholipid surfaces, initiating the coagulation cascade. Without adequate vitamin K₁, these proteins remain in an uncarboxylated, inactive form, leading to impaired clotting and an increased risk of hemorrhage. This mechanism is precisely what is targeted by anticoagulant medications like warfarin, which inhibit the vitamin K epoxide reductase complex subunit 1 (VKORC1), thereby depleting the active form of vitamin K and preventing carboxylation [7].

2.1.2 Role in Bone Metabolism

Beyond its hepatic functions, phylloquinone is also involved in bone metabolism, primarily through the carboxylation of osteocalcin, also known as bone Gla protein (BGP). Osteocalcin is a non-collagenous protein secreted by osteoblasts, the cells responsible for bone formation. Carboxylated osteocalcin is capable of binding calcium and hydroxyapatite, integrating into the bone matrix and playing a role in bone mineralization and maturation [8]. Inadequate vitamin K₁ status can lead to the production of undercarboxylated osteocalcin (ucOC), which has a reduced affinity for calcium and bone matrix, potentially compromising bone quality and increasing the risk of osteoporosis and fractures. While both K₁ and K₂ forms contribute to osteocalcin carboxylation, some research suggests distinct efficacies or specific roles for each [9].

2.2 Menaquinones (Vitamin K₂)

Menaquinones, collectively known as vitamin K₂, comprise a series of related compounds distinguished by isoprenoid side chains of varying lengths at the 3-position of the naphthoquinone ring. These are denoted as MK-n, where ‘n’ represents the number of isoprenoid units. The most commonly studied menaquinones include MK-4, MK-7, MK-9, and MK-10. Unlike phylloquinone, menaquinones are primarily synthesized by bacteria, both in the human gut and during food fermentation processes, and are also found in animal tissues [10].

2.2.1 Menaquinone-4 (MK-4)

MK-4 is unique among the menaquinones because it is largely formed in animal tissues through a metabolic conversion of dietary phylloquinone or other menaquinones, rather than direct dietary intake. This conversion involves the removal of the phytyl side chain of K₁ and the subsequent attachment of a geranylgeranyl pyrophosphate group [11]. The precise enzymatic machinery for this conversion, specifically the UBIAD1 enzyme, has been identified, highlighting the dynamic interplay between different vitamin K forms within the body [12].

MK-4 is found in various non-hepatic tissues, including the brain, testes, pancreas, arterial walls, and kidneys. Its presence in these extra-hepatic sites suggests specialized functions distinct from those of K₁ which primarily focuses on hepatic carboxylation. In the brain, MK-4 has been implicated in sphingolipid synthesis, a critical component of neuronal membranes, and may play a role in neurological health and protection against oxidative stress [13]. In the testes, MK-4 is involved in steroidogenesis, contributing to testosterone production. Furthermore, MK-4 exhibits potent anti-inflammatory and potentially anti-carcinogenic properties in various in vitro and in vivo models, independent of its γ-carboxylation cofactor activity, suggesting direct cellular signaling roles [14].

2.2.2 Long-Chain Menaquinones (MK-7, MK-9, etc.)

Long-chain menaquinones, such as MK-7, MK-8, and MK-9, are predominantly synthesized by bacteria and are found in fermented foods like natto and certain cheeses. These forms possess longer and more unsaturated isoprenoid side chains, which confer distinct pharmacokinetic properties, including a longer circulating half-life and superior bioavailability compared to K₁ and MK-4 [15]. This extended presence in circulation allows for more efficient delivery to extra-hepatic tissues, making them particularly effective in supporting bone and cardiovascular health.

Role in Cardiovascular Health

Long-chain menaquinones, especially MK-7, play a crucial role in preventing vascular calcification, a significant risk factor for cardiovascular diseases such as atherosclerosis and arterial stiffness. This is achieved through the activation of Matrix Gla Protein (MGP), a potent inhibitor of soft tissue calcification. MGP, synthesized in vascular smooth muscle cells and chondrocytes, requires vitamin K-dependent carboxylation to become biologically active [16]. In its uncarboxylated (inactive) form, MGP cannot effectively bind calcium or inhibit its deposition in arterial walls. Chronic subclinical vitamin K deficiency, particularly of K₂, leads to increased levels of uncarboxylated MGP (ucMGP), which has been strongly correlated with increased arterial stiffness and progression of coronary artery calcification [17]. Supplementation with MK-7 has shown promising results in several clinical trials, demonstrating a reduction in arterial stiffness and a slowdown in the progression of vascular calcification in various populations, including healthy adults and patients with chronic kidney disease [18].

Role in Bone Health

Similar to K₁, menaquinones are critical for bone health through the carboxylation of osteocalcin. However, given their superior bioavailability and longer half-life, especially MK-7, they are thought to be more effective in ensuring adequate carboxylation of osteocalcin and other bone-related Gla-proteins like Gla-rich protein (GRP) [19]. Studies, particularly in Japan where natto consumption is high, have linked higher intakes of MK-7 with improved bone mineral density (BMD) and reduced fracture risk in postmenopausal women. The sustained presence of MK-7 in circulation allows for continuous delivery to osteoblasts, supporting optimal bone remodeling and mineralization processes [20].

2.2.3 Emerging Roles of Menaquinones

Research continues to uncover additional functions for menaquinones. Their presence and specific activities in the brain suggest a role in cognitive function and neurodegenerative disease prevention, possibly through modulation of brain lipid metabolism and antioxidant defenses [13]. There is also growing interest in their potential anti-cancer properties, with several in vitro and in vivo studies demonstrating that menaquinones can induce apoptosis, inhibit proliferation, and suppress metastasis in various cancer cell lines, including liver, lung, and prostate cancers [21]. These effects appear to be concentration-dependent and may involve mechanisms distinct from their role as a γ-carboxylation cofactor.

2.3 The Vitamin K Cycle and Gamma-Carboxylation

The fundamental mechanism by which all forms of vitamin K exert their effects is through their participation in the vitamin K cycle, an elegant enzymatic process that allows for the efficient reuse of the vitamin. This cycle is essential for the continuous carboxylation of Glu residues in VKDPs [7].

The cycle begins with vitamin K hydroquinone (the reduced, active form of vitamin K), which acts as a cofactor for γ-glutamyl carboxylase (GGCX). During the carboxylation reaction, the GGCX converts Glu to Gla, while simultaneously oxidizing vitamin K hydroquinone to vitamin K epoxide. The vitamin K epoxide must then be reduced back to vitamin K quinone and subsequently to vitamin K hydroquinone to participate in further carboxylation reactions. This reduction is primarily catalyzed by vitamin K epoxide reductase complex subunit 1 (VKORC1) and, to a lesser extent, by NAD(P)H-dependent quinone reductases [7].

VKORC1 is the target of anticoagulant drugs like warfarin. By inhibiting VKORC1, warfarin prevents the regeneration of active vitamin K hydroquinone, leading to an accumulation of vitamin K epoxide and a reduction in the carboxylation of VKDPs, thereby impairing blood clotting. The efficiency of this cycle allows a relatively small amount of vitamin K to support a large number of carboxylation reactions, making vitamin K status highly dependent on a continuous supply, even if small.

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3. Dietary Sources and Bioavailability of Vitamin K

The primary chemical forms of vitamin K, phylloquinone (K₁) and menaquinones (K₂), originate from distinct dietary sources, leading to variations in their bioavailability and contribution to the body’s overall vitamin K status.

3.1 Phylloquinone Sources

Phylloquinone (K₁) is almost exclusively found in plant-based foods, particularly in green leafy vegetables, where it is concentrated in the chloroplasts as part of the photosynthetic machinery. The richness of K₁ in these foods is significant:

• Green Leafy Vegetables: Kale, spinach, collard greens, turnip greens, Swiss chard, mustard greens, parsley, and romaine lettuce are exceptionally rich sources. For instance, a single cup of raw kale can provide over 1000% of the Adequate Intake (AI) for K₁ [22]. Broccoli, Brussels sprouts, and asparagus also contain substantial amounts.
• Vegetable Oils: Certain vegetable oils, such as soybean oil, canola oil, and olive oil, are also good sources of K₁. The K₁ content in these oils can vary based on the specific plant source and processing methods [23].
• Other Plant Foods: Smaller amounts of K₁ can be found in some fruits (e.g., kiwifruit, avocado), but their contribution to total intake is generally less significant compared to green leafy vegetables.

3.1.1 Bioavailability of Phylloquinone

The bioavailability of phylloquinone from plant sources can be quite variable. K₁ is tightly bound within the chloroplast membranes of plant cells, requiring adequate chewing and digestive breakdown to release the vitamin. Furthermore, as a fat-soluble vitamin, its absorption is significantly enhanced by the presence of dietary fat [24]. Studies have shown that consuming K₁-rich vegetables with a source of fat (e.g., olive oil in a salad) can markedly improve its absorption efficiency. Without adequate fat, absorption can be as low as 4-10%. The cooking method can also influence availability; light steaming or sautéing might break down cell walls, potentially enhancing release, while excessive boiling may lead to some loss into cooking water.

3.2 Menaquinone Sources

Menaquinones (K₂) are a more diverse group, with their sources varying depending on the length of their isoprenoid side chain.

3.2.1 Menaquinone-4 (MK-4) Sources

MK-4 is found primarily in animal products, where it is believed to be largely synthesized from dietary K₁ within the animal’s tissues. It is present in:

• Meat: Particularly chicken and beef liver, but also in muscle meat.
• Eggs: The yolk is a notable source.
• Dairy Products: While K₁ is present in dairy fat (from the animal’s diet), MK-4 is also found, particularly in full-fat dairy and some cheeses [25].

3.2.2 Long-Chain Menaquinone (MK-7, MK-8, MK-9) Sources

Long-chain menaquinones are predominantly produced by bacterial fermentation. The most well-known source is natto, a traditional Japanese fermented soybean product, which is exceptionally rich in MK-7 due to the fermentation action of Bacillus subtilis [15]. Other fermented foods also contribute:

• Fermented Dairy: Certain cheeses, particularly Gouda, Brie, and other aged or mold-ripened cheeses, can contain significant amounts of MK-7, MK-8, and MK-9, synthesized by specific bacterial cultures [26]. Yogurt and kefir contain minimal amounts unless specific probiotic strains are used.
• Sauerkraut: Fermented cabbage may contain some menaquinones, though generally in lower concentrations than natto or specific cheeses.

3.2.3 Endogenous Production by Gut Microbiota

The human gut microbiota, particularly bacteria in the colon, are capable of synthesizing various menaquinones (MK-6 to MK-13) [27]. While this endogenous production contributes to the overall pool of vitamin K, the extent to which these bacterially produced menaquinones are absorbed and contribute to the body’s vitamin K status is a subject of ongoing debate. The primary site of fat-soluble vitamin absorption is the small intestine, whereas most menaquinone synthesis occurs in the colon. This anatomical separation may limit the systemic availability of gut-derived menaquinones, though some passive diffusion may occur, particularly with longer chain forms [27]. Factors such as individual gut microbiota composition, dietary fiber intake, and the use of antibiotics can significantly influence the quantity and types of menaquinones produced.

3.3 Factors Affecting Overall Vitamin K Bioavailability

Several factors can influence the overall bioavailability of dietary vitamin K:

• Dietary Fat: As discussed, fat is crucial for the absorption of all fat-soluble vitamins, including vitamin K. Meals with insufficient fat content will lead to reduced absorption.
• Food Matrix: The structure of the food itself (e.g., tough plant cell walls in green leafy vegetables) can impede the release and absorption of vitamin K₁.
• Digestive Health: Conditions affecting fat digestion and absorption, such as pancreatic insufficiency, bile acid malabsorption (e.g., due to cholestasis, inflammatory bowel disease, or celiac disease), or bariatric surgery, can significantly impair vitamin K absorption [28].
• Gut Microbiota: While a source of menaquinones, dysbiosis or antibiotic use can alter the balance of gut bacteria, potentially affecting endogenous K₂ production and overall vitamin K status.
• Genetic Factors: Polymorphisms in genes involved in vitamin K metabolism (e.g., VKORC1) can influence individual requirements and responsiveness to vitamin K intake.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Absorption, Transport, Metabolism, and Storage of Vitamin K

The journey of vitamin K from the diet to its cellular targets involves a complex series of processes critical for its biological activity. These mechanisms ensure that the various forms of vitamin K are effectively absorbed, distributed, utilized, and eventually excreted.

4.1 Absorption

Both phylloquinone and menaquinones are fat-soluble vitamins, and their absorption largely mirrors that of other dietary lipids. This process primarily occurs in the small intestine, specifically the jejunum and ileum [29].

1. Emulsification: Upon ingestion, dietary fats and vitamin K are emulsified by bile salts, which are produced by the liver and stored in the gallbladder. Pancreatic lipases then hydrolyze triglycerides, releasing fatty acids and monoglycerides.
2. Micelle Formation: Vitamin K, along with other fat-soluble vitamins, fatty acids, and monoglycerides, are incorporated into mixed micelles. These micelles are essential for transporting the hydrophobic vitamin K compounds through the aqueous environment of the intestinal lumen to the enterocyte brush border.
3. Enterocyte Uptake: Micelles approach the brush border of enterocytes, where vitamin K is absorbed into the mucosal cells. This uptake occurs primarily through passive diffusion, although carrier-mediated transport mechanisms for specific forms cannot be entirely ruled out [29].
4. Chylomicron Formation: Within the enterocytes, vitamin K is re-esterified with fatty acids and then packaged into nascent chylomicrons, large lipoprotein particles, along with other dietary fats and fat-soluble vitamins. The efficiency of absorption varies; while up to 80% of dietary K₁ can be absorbed under optimal conditions (e.g., with fat), the absorption of menaquinones, particularly long-chain forms like MK-7, is generally considered more efficient and sustained [15].

4.2 Transport

Once packaged into chylomicrons, vitamin K follows the lymphatic pathway before entering the systemic circulation:

1. Lymphatic System: Chylomicrons containing vitamin K are released from enterocytes into the lymphatic system, bypassing the portal circulation. They then enter the bloodstream via the thoracic duct.
2. Lipoprotein Distribution: In the circulation, chylomicrons deliver triglycerides to peripheral tissues. Chylomicron remnants, enriched with vitamin K and cholesterol, are then taken up by the liver. In the liver, vitamin K can be repacked into very-low-density lipoproteins (VLDL) and subsequently distributed to extra-hepatic tissues via low-density lipoproteins (LDL) and high-density lipoproteins (HDL) [30]. The distribution patterns of K₁ and K₂ differ, with K₁ predominantly associated with hepatic VLDL, while menaquinones, especially MK-7, show a greater association with LDL and HDL, allowing for more widespread systemic delivery and sustained circulation [15]. This difference in lipoprotein association contributes to the longer half-life and superior extra-hepatic bioavailability of MK-7.

4.3 Metabolism

The central metabolic process for vitamin K is the vitamin K cycle, which occurs primarily in the endoplasmic reticulum of cells, especially hepatocytes. As detailed in Section 2.3, this cycle involves the interconversion of vitamin K hydroquinone, vitamin K epoxide, and vitamin K quinone, allowing the vitamin to function as an enzymatic cofactor for γ-glutamyl carboxylase [7].

Beyond this functional cycle, vitamin K undergoes catabolism, leading to its eventual excretion. The catabolic pathways involve oxidative shortening of the isoprenoid side chains, followed by glucuronidation in the liver. These water-soluble glucuronide conjugates are then excreted via bile into the feces or via urine. The rate of catabolism and excretion can vary depending on the vitamin K form; phylloquinone generally has a shorter half-life and is more rapidly cleared than long-chain menaquinones [31].

4.4 Storage

The human body has a relatively limited storage capacity for vitamin K compared to other fat-soluble vitamins like A, D, or E. The liver is the primary storage site, holding approximately 90% of the body’s phylloquinone reserves [32]. However, these reserves are small, typically sufficient for only a few days to a week without dietary intake. This limited storage capacity underscores the need for a continuous dietary supply of vitamin K.

Menaquinones, particularly long-chain forms like MK-7, are also found in various extra-hepatic tissues, including bone, adipose tissue, brain, heart, and pancreas, where they are actively involved in local carboxylation reactions. While the liver’s storage of K₁ primarily supports hepatic coagulation factors, the widespread distribution and longer half-life of K₂ forms appear to be crucial for supporting extra-hepatic VKDPs, contributing to their distinct physiological roles [15]. The ability of the body to convert K₁ to MK-4 in certain tissues further highlights the dynamic nature of vitamin K metabolism and distribution.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Historical Context and Discovery of Vitamin K

The journey of discovering vitamin K is a fascinating chapter in nutritional science, marked by serendipitous observations, meticulous experimentation, and ultimately, the recognition of a new class of essential micronutrients.

5.1 The Initial Discovery of an Anti-Hemorrhagic Factor

The story of vitamin K begins in 1929 with the pioneering work of Danish biochemist Henrik Dam. While conducting experiments at the University of Copenhagen on cholesterol metabolism in chicks, Dam fed them a sterol-free diet [33]. After several weeks, he observed that these chicks developed a severe hemorrhagic diathesis, characterized by spontaneous bleeding in various tissues and prolonged blood clotting times. This bleeding tendency could not be corrected by re-administering cholesterol or other known vitamins.

Dam hypothesized the existence of a new fat-soluble nutrient essential for coagulation. He initially referred to this unknown factor as the ‘Koagulations-vitamin’, a term derived from the German spelling of ‘coagulation’, and thus, ‘vitamin K’ was born [33]. Over the subsequent years, Dam and his colleague F. Schønheyder performed extensive purification work, isolating the anti-hemorrhagic factor from alfalfa and putrefied fish meal. They demonstrated that the factor from alfalfa (later identified as phylloquinone, K₁) and that from putrefied fish meal (later identified as menaquinones, K₂) shared the same biological activity of restoring normal blood clotting.

Concurrently, independent research by H.J. Almquist and E.L.R. Stokstad in the United States confirmed Dam’s findings, observing similar hemorrhagic conditions in chicks fed specific diets and successfully identifying a factor from fish meal that prevented this [34].

5.2 Chemical Elucidation and Synthesis

The chemical characterization of vitamin K was achieved by the American biochemist Edward Adelbert Doisy and his team at Saint Louis University. In 1939, Doisy successfully isolated and elucidated the chemical structures of two distinct forms of vitamin K: vitamin K₁ (phylloquinone) from alfalfa and vitamin K₂ (a menaquinone, initially identified as MK-4) from putrefied fish meal [35]. His work revealed that both compounds were naphthoquinone derivatives, differing only in the chemical structure of their isoprenoid side chains.

Shortly after Doisy’s structural elucidation, Louis Fieser at Harvard University successfully synthesized vitamin K₁, confirming its structure. The rapid synthesis of vitamin K paved the way for its production and clinical application in treating hemorrhagic conditions. For their groundbreaking work in discovering vitamin K and elucidating its chemical nature, Henrik Dam and Edward Doisy were jointly awarded the Nobel Prize in Physiology or Medicine in 1943 [36].

5.3 Expansion of Roles Beyond Coagulation

For several decades following its discovery, the primary focus of vitamin K research remained on its role in blood coagulation. However, the 1970s marked a significant turning point with the discovery of osteocalcin (bone Gla protein – BGP), the first non-coagulation vitamin K-dependent protein [8]. This discovery unequivocally demonstrated that vitamin K’s physiological functions extended beyond hemostasis and were crucial for bone metabolism. Subsequently, in the 1980s, Matrix Gla Protein (MGP) was identified, revealing vitamin K’s critical involvement in regulating soft tissue calcification, particularly in the vasculature [16].

These discoveries led to the recognition of the ‘vitamin K paradox’ – a situation where an individual might have sufficient vitamin K for optimal blood clotting (a function primarily dependent on hepatic K₁), but insufficient levels for optimal functioning of extra-hepatic VKDPs involved in bone and cardiovascular health (functions more sensitive to menaquinones, particularly long-chain K₂ forms) [4]. This paradox fueled intensive research into the distinct roles and requirements of K₁ and K₂, leading to a more nuanced understanding of this once coagulation-centric vitamin. Modern research continues to uncover new VKDPs and expand our appreciation of vitamin K’s pervasive influence on human health.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Vitamin K Deficiency, Subclinical Insufficiency, and Health Implications

While frank vitamin K deficiency leading to severe bleeding is relatively rare in healthy adults, subclinical vitamin K insufficiency, particularly affecting the carboxylation of extra-hepatic vitamin K-dependent proteins, is increasingly recognized as a widespread issue with significant long-term health implications [4, 17].

6.1 Hemorrhagic Disorders (Coagulation)

The most dramatic and acutely dangerous manifestation of vitamin K deficiency is impaired blood clotting, leading to excessive bleeding.

6.1.1 Vitamin K Deficiency Bleeding (VKDB) in Newborns

Newborn infants are particularly vulnerable to VKDB, formerly known as hemorrhagic disease of the newborn. This susceptibility stems from several factors:

• Low Placental Transfer: Vitamin K does not efficiently cross the placenta, resulting in low fetal and neonatal vitamin K stores.
• Immature Liver: The neonatal liver has immature enzymatic systems for vitamin K metabolism and synthesis of coagulation factors.
• Sterile Gut: Newborns are born with a sterile gut, lacking the bacteria necessary for endogenous menaquinone synthesis, which typically develops over weeks to months.
• Low Vitamin K in Breast Milk: Human breast milk contains relatively low levels of vitamin K, making exclusively breastfed infants particularly susceptible if not supplemented [37].

VKDB can present in various forms:

• Early VKDB: Occurs within the first 24 hours of birth, often severe, associated with maternal medication use (e.g., anticonvulsants, antituberculosis drugs) that interferes with vitamin K metabolism.
• Classical VKDB: Occurs between day 1 and 7, typically presenting with gastrointestinal bleeding, umbilical stump bleeding, or skin bruising.
• Late VKDB: Occurs between weeks 2 and 12 (or even up to 6 months), primarily in exclusively breastfed infants who did not receive vitamin K prophylaxis at birth. This form is often the most dangerous due to a high incidence of intracranial hemorrhage, leading to severe neurological damage or death [37].

Due to these risks, the prophylactic administration of a single intramuscular dose of vitamin K to all newborns at birth is a universal standard of care, effectively preventing VKDB [38].

6.1.2 Adult Deficiency and Risk Factors

While VKDB is rare in healthy adults, certain conditions and medications can predispose individuals to deficiency:

• Malabsorption Syndromes: Conditions that impair fat absorption, such as cystic fibrosis, celiac disease, inflammatory bowel disease (Crohn’s disease, ulcerative colitis), chronic pancreatitis, or biliary obstruction (cholestasis), can significantly reduce vitamin K absorption [28].
• Liver Disease: Severe liver disease impairs the synthesis of vitamin K-dependent clotting factors, even with adequate vitamin K intake, leading to coagulopathy.
• Chronic Antibiotic Use: Prolonged broad-spectrum antibiotic therapy can suppress gut bacteria that produce menaquinones, potentially contributing to deficiency, although the clinical significance of this effect is debated given the limited contribution of gut-synthesized K₂ to systemic status [27].
• Bariatric Surgery: Gastric bypass or other malabsorptive bariatric procedures can compromise vitamin K absorption.
• Medications: Warfarin (a vitamin K antagonist) is intentionally used to induce a functional vitamin K deficiency for therapeutic anticoagulation. Overdose or inconsistent intake can lead to hemorrhagic complications. Salicylates in very high doses, certain anticonvulsants, and some cephalosporin antibiotics can also interfere with vitamin K metabolism [39].

Symptoms of adult vitamin K deficiency include easy bruising, nosebleeds, bleeding gums, excessive bleeding from wounds, blood in urine or stool, and heavy menstrual bleeding (menorrhagia).

6.2 Bone Health

Inadequate vitamin K status, even without overt bleeding, is increasingly recognized as a risk factor for compromised bone health, contributing to osteoporosis and increased fracture risk.

6.2.1 Mechanism

Vitamin K’s role in bone health is primarily mediated through its activation of osteocalcin (bone Gla protein, BGP) and matrix Gla protein (MGP). Osteocalcin, produced by osteoblasts, requires carboxylation to bind calcium and integrate into the bone matrix, where it plays a role in bone mineralization and structural integrity [8]. When vitamin K status is suboptimal, osteocalcin remains undercarboxylated (ucOC), impairing its function and potentially leading to weaker bones.

6.2.2 Evidence and Clinical Implications

Numerous observational studies have demonstrated an association between lower vitamin K intake or status (measured by ucOC or uncarboxylated MGP) and decreased bone mineral density (BMD) and an elevated risk of hip and vertebral fractures, particularly in postmenopausal women [9].

Intervention studies, particularly those utilizing menaquinones (MK-4 and MK-7), have shown promising results. In Japan, high doses of MK-4 are approved for the treatment of osteoporosis, and clinical trials have indicated its efficacy in reducing fracture incidence. Studies with MK-7, due to its superior bioavailability and longer half-life, have also shown improvements in bone turnover markers, reductions in ucOC, and in some cases, improvements in BMD, suggesting a critical role for optimal menaquinone status in maintaining skeletal integrity [20].

6.3 Cardiovascular Health

Perhaps one of the most significant and relatively recent expansions of vitamin K’s known functions is its critical role in cardiovascular health, particularly in inhibiting arterial calcification.

6.3.1 Mechanism

The primary mechanism involves Matrix Gla Protein (MGP), a potent calcification inhibitor produced by vascular smooth muscle cells and chondrocytes. MGP requires vitamin K-dependent carboxylation to become biologically active and effectively bind to calcium, thereby preventing its deposition in the arterial walls and other soft tissues [16]. When vitamin K status is insufficient, MGP remains undercarboxylated (ucMGP), rendering it inactive and unable to perform its protective role. This leads to unopposed calcium deposition, contributing to arterial stiffness and the development and progression of atherosclerosis [17].

6.3.2 Evidence and Clinical Implications

Prospective epidemiological studies have consistently shown an inverse association between higher intakes of dietary menaquinones (K₂) and the risk of coronary artery calcification (CAC), aortic calcification, arterial stiffness, and cardiovascular events, including myocardial infarction and cardiovascular mortality [17]. The Rotterdam Study, a landmark population-based cohort study, was among the first to highlight this association, demonstrating that high dietary intake of MK-7, MK-8, and MK-9 was protective against aortic calcification and cardiovascular mortality in older adults [40].

Clinical trials, particularly with MK-7 supplementation, have provided compelling evidence. A three-year randomized controlled trial showed that MK-7 supplementation significantly reduced arterial stiffness and improved vascular elasticity in healthy postmenopausal women, with a notable reduction in ucMGP levels [18]. These findings suggest that optimizing vitamin K status, especially with long-chain menaquinones, is crucial for maintaining vascular health and may be a modifiable risk factor for cardiovascular disease.

6.4 Other Emerging Roles and Implications

Beyond coagulation, bone, and cardiovascular health, research is uncovering further intriguing roles for vitamin K:

• Neurological Health: High concentrations of MK-4 are found in the brain, where it participates in the synthesis of sphingolipids, which are crucial components of neuronal cell membranes and myelin sheaths [13]. Some studies suggest MK-4 may have neuroprotective effects, potentially mitigating oxidative stress and inflammation in the brain, and may play a role in preventing neurodegenerative diseases like Alzheimer’s and Parkinson’s. While more research is needed, this area holds significant promise.
• Renal Health: Gla-rich protein (GRP) is another VKDP primarily expressed in the kidneys, cartilage, and vascular tissues. It acts as a calcification inhibitor. Dysregulation of GRP, potentially linked to vitamin K insufficiency, has been implicated in renal calcification and calciphylaxis, a severe condition seen in patients with end-stage renal disease [41].
• Cancer: Preliminary research indicates that vitamin K, particularly menaquinones, may possess anti-cancer properties. In vitro and in vivo studies have shown that K₂ forms can induce apoptosis (programmed cell death), inhibit cell proliferation, and suppress metastasis in various cancer cell lines, including hepatocellular carcinoma, lung cancer, and prostate cancer [21]. These effects appear to be independent of their γ-carboxylation activity and may involve direct signaling pathways, making vitamin K a potential candidate for adjuvant cancer therapies, although clinical evidence is still limited.
• Insulin Sensitivity and Diabetes: Emerging evidence suggests a potential link between vitamin K status and insulin sensitivity. Some studies have indicated that higher vitamin K intake or supplementation might improve glucose metabolism and insulin sensitivity, possibly through its effects on osteocalcin (which influences pancreatic beta-cell function and insulin secretion) or through anti-inflammatory mechanisms [42].
• Inflammation: Vitamin K has been shown to exert anti-inflammatory effects by inhibiting the activity of NF-κB, a central regulator of inflammatory responses, and by reducing levels of pro-inflammatory cytokines. This anti-inflammatory action may contribute to its protective roles in various chronic diseases [14].

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. Recommended Dietary Intake and Supplementation

Establishing recommended dietary intakes for vitamin K is complex due to the existence of multiple vitamers with distinct biological activities and varying contributions to health outcomes. Current recommendations primarily focus on phylloquinone, reflecting its abundance in the Western diet and its well-established role in coagulation.

7.1 Current Dietary Reference Intakes (DRIs)

The Food and Nutrition Board of the Institute of Medicine (now the National Academy of Medicine) established Adequate Intake (AI) levels for vitamin K in the United States and Canada [43]. These values are based on median phylloquinone intakes in apparently healthy populations and are set at levels presumed to ensure adequate hepatic carboxylation to prevent bleeding disorders.

• Adult Males (19+ years): 120 micrograms (mcg) per day
• Adult Females (19+ years): 90 micrograms (mcg) per day
• Pregnancy and Lactation: 90 micrograms (mcg) per day
• Infants (0-6 months): 2.0 mcg per day (based on breast milk intake)
• Infants (7-12 months): 2.5 mcg per day
• Children (1-3 years): 30 mcg per day
• Children (4-8 years): 55 mcg per day
• Children (9-13 years): 60 mcg per day
• Adolescents (14-18 years): 75 mcg per day

The European Food Safety Authority (EFSA) also provides a Scientific Opinion on Dietary Reference Values for vitamin K, recommending 70 mcg/day for adults, based on observed intakes and maintaining normal blood coagulation [44].

Crucially, these recommendations do not differentiate between phylloquinone and menaquinones, nor do they specifically address the requirements for extra-hepatic vitamin K-dependent proteins critical for bone and cardiovascular health. They are primarily set to prevent clinical bleeding, not necessarily to optimize the functions of all VKDPs [4]. This has led to a growing consensus among researchers that current AIs may be sufficient for hepatic coagulation, but potentially inadequate for extra-hepatic processes that are more sensitive to menaquinone status.

7.2 Adequacy of Intake and Subclinical Insufficiency

Most healthy individuals consuming a balanced diet rich in green leafy vegetables are likely to meet the AI for phylloquinone. However, dietary surveys often report that a significant portion of the population, particularly adolescents and older adults, may not consume sufficient amounts of K₁-rich foods [45].

Furthermore, dietary intake of long-chain menaquinones (e.g., MK-7) is highly variable and often low in Western diets, primarily relying on fermented foods like natto which are not widely consumed. As such, subclinical vitamin K insufficiency, characterized by elevated levels of undercarboxylated osteocalcin (ucOC) and uncarboxylated matrix Gla protein (ucMGP), is prevalent across various age groups and populations [17]. This suggests that while overt bleeding is rare, many individuals may not be achieving optimal vitamin K status for bone and cardiovascular protection, highlighting the ‘vitamin K paradox’.

7.3 Vitamin K Supplementation

Given the emerging understanding of vitamin K’s broad health benefits and the prevalence of subclinical insufficiency, supplementation with specific forms of vitamin K is becoming increasingly popular and studied.

7.3.1 Forms and Dosages

• Vitamin K₁ (Phylloquinone): Supplements typically contain K₁ in microgram doses (e.g., 100-1000 mcg). It is effective in preventing and treating coagulation disorders but has a shorter half-life and less efficient extra-hepatic distribution compared to long-chain K₂ forms. It is generally not recommended for bone or cardiovascular benefits as a primary intervention unless K₂ is unavailable.
• Vitamin K₂ (Menaquinones):
  • MK-4: Typically available in milligram doses (e.g., 1.5 mg to 45 mg), reflecting its use in Japan for osteoporosis treatment. While effective for bone, its very short half-life necessitates multiple daily doses to maintain sufficient tissue levels [11].
  • MK-7: This form is highly favored for supplementation due to its superior bioavailability and long circulating half-life (approximately 3 days), allowing for once-daily dosing and efficient delivery to extra-hepatic tissues [15]. Typical doses for bone and cardiovascular health range from 45 mcg to 360 mcg per day, depending on the specific health goal and individual status [18, 20].
  • MK-9: Less commonly available as a standalone supplement, but present in some fermented foods and multi-K₂ formulations.

7.3.2 Safety and Tolerability

Both phylloquinone (K₁) and menaquinones (K₂) have a very low toxicity profile. No Upper Limit (UL) has been established for either natural form of vitamin K, as there is no evidence of adverse effects from high intakes [43]. However, menadione (synthetic vitamin K₃), a water-soluble analogue, is toxic and can cause hemolytic anemia and liver damage, thus it is not used in supplements or food fortification.

7.3.3 Drug Interactions

The most critical drug interaction is with warfarin (Coumadin®), a vitamin K antagonist. Individuals on warfarin therapy must maintain a consistent daily intake of vitamin K, as sudden fluctuations can destabilize their International Normalized Ratio (INR) and increase the risk of bleeding (if K intake increases) or clotting (if K intake decreases). Supplementation with vitamin K (especially K₁) can counteract warfarin’s effects and is sometimes used to reverse excessive anticoagulation [7]. Patients on warfarin should consult their healthcare provider before making significant dietary changes or initiating any vitamin K supplement. Newer oral anticoagulants (DOACs or NOACs) like dabigatran, rivaroxaban, apixaban, and edoxaban work via different mechanisms and are not affected by vitamin K intake.

7.3.4 Synergistic Nutrients

Vitamin K’s functions, particularly in bone and cardiovascular health, are often synergistic with other nutrients:

• Vitamin D: Both vitamins D and K are essential for calcium homeostasis. Vitamin D promotes calcium absorption, while vitamin K directs calcium to appropriate tissues (bones and teeth) and away from soft tissues (arteries). Several VKDPs, including osteocalcin, are also regulated by vitamin D, highlighting their metabolic interplay [46]. Co-supplementation of D and K is often recommended for optimal bone and cardiovascular health.
• Calcium: Adequate calcium intake is essential for bone mineralization, and vitamin K ensures that this calcium is effectively utilized in the bone matrix.
• Magnesium: Magnesium is involved in hundreds of enzymatic reactions, including those related to bone formation and energy metabolism, and works in conjunction with calcium and vitamin D.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

8. Future Directions and Research Gaps

Despite significant advances in our understanding of vitamin K, several critical areas warrant further investigation to fully unlock its therapeutic potential and optimize public health recommendations.

8.1 Differentiating Requirements for K₁ and K₂

One of the most pressing research needs is to establish specific Recommended Dietary Allowances (RDAs) for individual vitamin K forms, particularly distinguishing between phylloquinone and the various menaquinones. Current AIs are predominantly based on K₁’s role in coagulation, neglecting the distinct extra-hepatic functions of K₂. Future research should aim to define optimal intake levels for K₁ and specific K₂ forms (e.g., MK-4, MK-7) to support optimal bone, cardiovascular, and other emerging health outcomes, moving beyond a coagulation-centric view [4].

8.2 Optimal Dosages for Specific Health Outcomes

Rigorous, long-term randomized controlled trials are needed to determine the optimal dosages of specific menaquinones, especially MK-7, for the prevention and treatment of osteoporosis, cardiovascular calcification, and other chronic diseases. While some promising intervention studies exist, larger trials with diverse populations and longer durations are essential to solidify evidence-based recommendations for clinical practice.

8.3 Role of Gut Microbiota in Menaquinone Status

The precise contribution of gut microbiota-synthesized menaquinones to systemic vitamin K status remains an area of active research. Factors influencing this contribution, such as the specific composition of the gut microbiome, dietary fiber intake, and individual genetic predispositions, need further elucidation. Understanding this complex interplay could inform personalized dietary strategies and probiotic interventions.

8.4 Genetic Variations and Personalized Nutrition

Genetic polymorphisms in genes involved in vitamin K metabolism (e.g., VKORC1, GGCX) can influence individual requirements and responses to vitamin K intake and supplementation [47]. Research into pharmacogenomics and nutrigenomics of vitamin K could pave the way for personalized dietary and supplementation recommendations, particularly for individuals at higher risk of deficiency or those on anticoagulant therapy.

8.5 Biomarkers for Vitamin K Status

Improved and readily available biomarkers that reflect whole-body vitamin K status, rather than just hepatic coagulation function, are crucial. While plasma ucOC and ucMGP are currently the best indicators of functional vitamin K status for bone and cardiovascular health, respectively, developing more comprehensive and integrated biomarkers could enhance the assessment of an individual’s vitamin K sufficiency across all systems [17].

8.6 Exploration of New Vitamin K-Dependent Proteins

The ongoing discovery of novel vitamin K-dependent proteins suggests that the full spectrum of vitamin K’s biological functions is yet to be fully uncovered. Continued research into the identification and characterization of new VKDPs will further broaden our understanding of this vitamin’s pervasive influence on human physiology.

8.7 Broader Clinical Applications

Further clinical trials are warranted to explore vitamin K’s potential roles in areas such as neurological health, anti-cancer therapy (as an adjuvant), diabetes management, and chronic inflammatory conditions. Moving from preclinical observations to robust clinical evidence is a critical next step in these emerging fields.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

9. Conclusion

Vitamin K, once primarily understood as a coagulation factor, has revealed itself to be a vital, multifaceted nutrient with profound implications for human health. The distinction between its primary forms, phylloquinone (K₁) and the diverse menaquinones (K₂), is fundamental to appreciating its broad physiological impact. While K₁ remains essential for hepatic blood clotting factors, long-chain menaquinones, particularly MK-7, are increasingly recognized for their superior bioavailability and critical roles in supporting extra-hepatic vitamin K-dependent proteins crucial for bone mineralization and the prevention of vascular calcification.

The historical trajectory of vitamin K’s discovery, from Henrik Dam’s observations of hemorrhagic chicks to Doisy’s chemical elucidation and the subsequent identification of non-coagulation Gla-proteins, underscores a continuous evolution in our scientific understanding. Despite current dietary recommendations primarily focusing on phylloquinone for coagulation, the pervasive prevalence of subclinical vitamin K insufficiency, particularly affecting bone and cardiovascular health, necessitates a re-evaluation of public health guidelines to adequately address the requirements for menaquinones.

Ensuring adequate intake of vitamin K, through a balanced diet rich in green leafy vegetables and, where appropriate, fermented foods or supplementation with menaquinones, is paramount for maintaining optimal health throughout the lifespan. Future research, focusing on the distinct requirements of K-vitamers, their synergistic interactions with other nutrients like vitamin D, and their emerging roles in neurological and cellular health, promises to further solidify vitamin K’s standing as an indispensable nutrient for comprehensive well-being. The journey of understanding vitamin K is far from complete, yet its established contributions already mark it as a cornerstone of preventive medicine and nutritional science.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

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