Vitamin_K
Vitamin K: Biological Functions, Clinical Significance, and Common Deficiency Manifestations
1. Introduction
Vitamin K is a fat‑soluble group of compounds that plays an indispensable role in haemostasis, bone metabolism, vascular health, and cellular signalling. The two principal naturally occurring forms are phylloquinone (vitamin K₁), obtained mainly from green leafy vegetables, and menaquinones (vitamins K₂), produced by intestinal microbiota and present in fermented foods such as natto and cheese. Although historically recognised for its coagulation function, contemporary research has expanded the scope of vitamin K to include bone integrity, arterial calcification inhibition, and modulation of inflammatory pathways.
2. Molecular Mechanisms Underlying Vitamin K Function
| Pathway | Key Components | Physiological Outcome |
|---|---|---|
| Coagulation cascade | γ‑glutamyl carboxylase (GGCX) → vitamin K epoxide reductase complex 1 (VKORC1) | Post‑translational carboxylation of glutamic acid residues on clotting factors II, VII, IX, X, and proteins C & S; activation of these proteins for fibrin formation. |
| Bone metabolism | Osteocalcin (OC), matrix Gla protein (MGP); vitamin K‑dependent γ‑carboxylation | Calcium binding to bone matrix; inhibition of ectopic calcification in arteries. |
| Cellular signalling | Protein S‑phosphorylation, nuclear receptor coactivators | Modulation of gene expression involved in inflammation and apoptosis. |
Vitamin K acts as a cofactor for the enzyme GGCX, which converts specific glutamate residues to γ‑carboxyglutamate (Gla). This post‑translational modification imparts calcium‑binding capacity essential for protein function.
3. Dietary Sources and Bioavailability
| Form | Food Sources | Typical Daily Intake (UK/US) | Factors Influencing Absorption |
|---|---|---|---|
| Vitamin K₁ (phylloquinone) | Spinach, kale, broccoli, Brussels sprouts, lettuce | 60–80 µg/day (women), 90–120 µg/day (men) | Lipid content of meal, intestinal microbiota composition, age, gastrointestinal health. |
| Vitamin K₂ – MK‑4 | Egg yolk, liver, dairy (especially hard cheeses) | ~5–10 µg/day | Short half‑life (~1 h), high tissue distribution in brain and bone. |
| Vitamin K₂ – MK‑7 to MK‑13 | Natto, fermented soy, certain cheeses, some fish | 100–200 µg/day (nattō) | Longer half‑life (3–4 days), better bioavailability for extra‑hepatic tissues. |
High‑fat meals enhance the absorption of all vitamin K forms due to their lipophilicity. Conversely, malabsorption syndromes such as cystic fibrosis or chronic pancreatitis can markedly reduce vitamin K uptake.
4. Clinical Benefits
4.1 Anticoagulation and Bleeding Prevention
- Prothrombin Time (PT) / International Normalized Ratio (INR): Adequate vitamin K status keeps INR within therapeutic range for patients on warfarin or other vitamin K antagonists, reducing the risk of both thrombosis and major bleeding.
- Platelet Function: Vitamin K influences platelet aggregation through γ‑carboxylation of proteins involved in thrombus formation.
4.2 Bone Health
- Osteocalcin Carboxylation: Fully carboxylated osteocalcin binds calcium, promoting mineralisation and reducing fracture risk.
- Clinical Trials: Supplementation with MK‑7 (≥180 µg/day) over 12–24 months has shown significant reductions in vertebral and non‑vertebral fractures among postmenopausal women.
4.3 Cardiovascular Protection
- Matrix Gla Protein (MGP): Vitamin K‑dependent activation of MGP inhibits vascular calcification, a key contributor to atherosclerosis.
- Epidemiological Evidence: Higher dietary intake of vitamin K₂ correlates with lower coronary artery calcium scores and reduced incidence of cardiovascular events.
4.4 Other Emerging Roles
- Cancer Prevention: In vitro studies suggest that vitamin K may induce apoptosis in colorectal cancer cells via modulation of the PI3K/AKT pathway.
- Neuroprotection: MK‑4 is enriched in brain tissue; animal models indicate a role in reducing amyloid deposition and oxidative stress.
5. Clinical Symptoms of Vitamin K Deficiency
| System | Symptom | Pathophysiology |
|---|---|---|
| Haemostasis | Prolonged bleeding from mucosal surfaces, easy bruising | Inadequate γ‑carboxylation → inactive clotting factors II, VII, IX, X. |
| Neonatal Period | Vitamin K deficiency bleeding (VKDB) – intracranial haemorrhage, petechiae | Newborns have low maternal stores and immature gut flora; prophylactic vitamin K injection is standard of care. |
| Bone Health | Osteopenia/osteoporosis, increased fracture risk | Suboptimal osteocalcin carboxylation → impaired bone mineralisation. |
| Cardiovascular | Accelerated arterial calcification (elevated calcium‑phosphate product) | Insufficient MGP activation leads to ectopic mineral deposition. |
Risk Factors for Deficiency:
- Premature infants, lactating mothers, chronic liver disease, malabsorption syndromes, long‑term antibiotic use (disrupts gut microbiota), high‑fat diets with low vitamin K content.
6. Diagnostic Evaluation
- Functional Tests
- Prothrombin Time (PT) and INR for hepatic synthesis of clotting factors.
- PIVKA‑II (protein induced by vitamin K absence or antagonism‑II) – elevated in deficiency.
- Biochemical Markers
- Serum levels of total vitamin K are unreliable due to rapid redistribution; hence functional assays are preferred.
- Bone Mineral Density (BMD)
- Dual-energy X-ray absorptiometry (DXA) to assess osteopenia/osteoporosis when deficiency is suspected.
7. Management Strategies
| Approach | Details |
|---|---|
| Dietary Modification | Increase intake of green leafy vegetables and fermented foods; ensure adequate fat for absorption. |
| Supplementation | MK‑7 180–360 µg/day for bone health; lower doses (≤100 µg/day) acceptable for general maintenance. |
| Pharmacologic Considerations | Patients on warfarin require careful monitoring of INR when vitamin K intake changes; dose adjustments may be necessary. |
| Parenteral Administration | For infants or patients with severe malabsorption, intramuscular vitamin K1 (0.5–1 mg) is standard prophylaxis. |
8. Future Directions
- Personalised Nutrition: Genomic variants in VKORC1 and GGCX may influence individual requirements; pharmacogenomics could tailor supplementation doses.
- Vitamin K₂ Formulation Development: Research into long‑acting MK‑7 or MK‑10 analogues aims to optimise arterial protection while minimising bleeding risk.
- Clinical Trials on Non‑Coagulation Outcomes: Large-scale, randomized studies are needed to confirm cardiovascular and neuroprotective benefits observed in observational data.
9. Conclusion
Vitamin K is a multifaceted nutrient whose adequacy ensures proper blood clotting, bone integrity, and vascular health. Deficiency manifests clinically across several systems, with bleeding disorders being the most acute presentation. Current evidence supports dietary emphasis on both vitamin K₁ and K₂ sources, while supplementation should be individualized based on clinical context and risk factors. Continued research will refine our understanding of vitamin K’s broader therapeutic potential beyond haemostasis.