Vitamin K2-MK4

Vitamin K is a significant but often underappreciated nutrient. Essential for various bodily functions, Vitamin K's role extends beyond its well-known contribution to blood clotting. 

Vitamin K, existing in two primary forms – K1 (phylloquinone) and K2 (menaquinones) – plays a pivotal role in health. 

The group of vitamins that comprise vitamin K2 are called menaquinones, and they hold diverse roles in human health.  Vitamin K2 plays multifaceted roles in bone metabolism, cardiovascular health, and emerging evidence points to its many other beneficial roles in human health. 

Vitamin K2, also known as menaquinone, is a group of compounds largely obtained from dietary sources. Among its several forms, Vitamin K2-MK4 (menaquinone-4) is a notable variant. 

This article explores the functions of vitamin K2-MK4 more specifically as a biomarker by delving into its functions, dietary sources, and daily requirements, and discussing the significance of lab testing for Vitamin K and related biomarkers.

Definition and Function of Vitamin K2-MK4

What is Vitamin K2-MK4?  [6., 13.]

Vitamin K2-MK4, or vitamin K2 as menaquinone-4, is a subtype of Vitamin K2. Its structure is characterized by a shorter side chain compared to other menaquinones, such as MK7.  The shorter side chain length influences its absorption and metabolism in the body. 

It is distinct from other forms of vitamin K2 due to its unique structure with four isoprene units in the side chain, making it more hydrophobic and readily absorbed in the body. 

It is known for being rapidly absorbed and utilized by the body but also has a shorter half-life compared to other forms like MK7.  This means that it needs to be consumed more frequently to maintain its levels in the body. 

Vitamin K2-MK4, or menaquinone-4, is derived from animal sources such as meat, liver, eggs, and dairy products. Unlike other forms of vitamin K2, MK4 is not typically produced by bacterial fermentation.  However, it can be directly synthesized from vitamin K1 in human and animal tissues.  [16., 17.]

Absorption of MK4 occurs mainly in the small intestine, with absorption rates influenced by factors like dietary fat content and bile secretion. 

Function of Vitamin K2-MK4 and Its Role In Health  [6., 8., 10.]

As a form of vitamin K2, Vitamin K2-MK4 is understood to have many of the same functions attributed to vitamin K2, including:

Bone Health: vitamin K2-MK4 plays a pivotal role in bone metabolism. It is essential for the activation of osteocalcin, a protein that binds calcium to the bone matrix, thus contributing to stronger bones and reducing the risk of fractures.

Cardiovascular Health: Vitamin K2 inhibits arterial calcification. By activating Matrix Gla Protein (MGP), it helps prevent calcium deposition in the arteries, thereby supporting cardiovascular health.

‍Anti-Inflammatory Properties: vitamin K2 exhibits anti-inflammatory effects by modulating the expression of inflammatory mediators and cytokines, thereby contributing to overall immune health and reducing the risk of chronic inflammatory conditions.

Dental Health: low vitamin K2 levels are associated with the development of periodontal diseases.  [15.]

Cancer Prevention: some studies suggest that vitamin K2 may play a role in cancer prevention, particularly in reducing the risk of certain types of cancer such as breast and liver cancers, as well as leukemia and possibly other cancer types.  Further research is needed to elucidate its mechanisms and efficacy in this regard.  [9.]

Vitamin K2-MK4 may also have a role in maintaining cognitive function: 

Neurological Health and Cognitive Function: within the brain, vitamin K2-MK4 influences cellular signaling pathways by promoting the carboxylation of proteins such as growth arrest-specific protein 6 (Gas6) and protein S, which are involved in neuronal survival, synaptic function, and neuroprotection.  [11.]

What is the Difference Between Vitamin K2-MK4 vs. MK7?

Vitamin K2 is a group of vitamins known as menaquinones.  Vitamin K2-MK4 (menaquinone-4) and vitamin K2-MK7 (menaquinone-7) are two of the most well-known and well-researched forms of vitamin K2. 

These two forms have garnered significant interest in nutritional science due to their distinct characteristics and impacts on human health. 

Bioavailability and Metabolism

Absorption: 

MK4 is rapidly absorbed but also quickly cleared from the bloodstream, requiring more frequent consumption for sustained levels.  MK4 can also be created in human tissues.  [16., 17.]

MK7, with its longer side chain, has a longer half-life and remains in the bloodstream longer, ensuring more consistent blood levels.

Differences in Function and Health Outcomes: Is Vitamin K2-MK4 or Vitamin K2-MK7 Better?

Vitamin K2, including both MK-4 and MK-7 forms, contributes to various physiological processes in the body and both have positive health effects. 

Bone Health

Both vitamin K2-MK4 and vitamin K2-MK7 play essential roles in bone health, but they exhibit some differences, which are likely due to their different bioavailabilities.  

Both activate osteocalcin, a protein essential for proper bone mineralization. This activation process ensures that calcium is effectively incorporated into the bone matrix, thereby promoting bone strength and density.  Both also enhance osteoblast activity, which is essential for building new bone tissue.   [5., 16.]

Vitamin K2-MK4 has a shorter half-life in the body compared to vitamin K2-MK7, leading to differences in dosing frequency. Generally, MK7 is noted for its prolonged action due to better bioavailability, but MK4’s fast-acting nature is beneficial for certain immediate physiological needs.

Additionally, studies suggest that vitamin K2-MK7 may have superior bioavailability and efficacy in promoting bone health compared to vitamin K2-MK4.  [16.]

Cardiovascular Health  [17.]

Vitamin K2-MK4 and K2-MK7 both offer cardiovascular benefits, but they may act through different mechanisms. 

While K2-MK7 has been primarily associated with reducing arterial calcification and improving vascular elasticity, K2-MK4 has shown potential in inhibiting the formation of cholesterol-induced arterial plaques. 

Additionally, K2-MK4 has been linked to reducing the risk of atherosclerosis and lowering the levels of low-density lipoprotein (LDL) cholesterol. Both forms of vitamin K2 contribute to cardiovascular health, but their specific roles and mechanisms of action may vary.

The choice between MK4 and MK7 may depend on individual health goals, dietary preferences, and specific health conditions. Some experts recommend a combination of both forms for a comprehensive approach to health.

Dietary Sources of Vitamin K2-MK4

While supplements are a common way to increase Vitamin K2-MK4 intake, understanding and utilizing dietary sources is crucial for a holistic approach to nutrition.

Animal-Based Sources of Vitamin K2-MK4

Meats: meats, particularly organ meats like liver and kidney, are excellent sources of Vitamin K2-MK4. 

Dairy Products: some dairy products contain significant levels of MK4. The type of dairy product – cheese, butter, or yogurt – can affect the amount of Vitamin K2-MK4, with fermented cheeses including Muenster, Camembert, Brie and aged Gouda typically having higher contents.

Eggs: Egg yolks are another good source of Vitamin K2-MK4, particularly when the hens are fed a diet rich in this vitamin. The nutrient content can vary based on the hen's diet and the egg's preparation method.

Vitamin K2 Supplements

For individuals who struggle to get enough Vitamin K2 from their diet, supplements can be a viable option. 

Supplements containing vitamin K2 often come in two forms: MK-4 and MK-7. MK-4 supplements are synthetic and have a shorter half-life, while MK-7, derived from natto, is natural and remains active in the body longer.

Vitamin K2 from Dietary Sources vs. Supplements

For those who can maintain a diet rich in Vitamin K2 (through cheese, natto, egg yolks, and meat), supplementation may not be necessary. Individuals who have dietary restrictions, such as vegans or those who have allergies to dairy or eggs, might find it challenging to get enough Vitamin K2 from diet alone and may consider supplements.

Recommended Vitamin K Intake

RDA of Vitamin K: How Much K2 Should I Get Per Day?  [14.]

The Recommended Dietary Allowance (RDA) for vitamin K varies based on age and gender.  There is no recommendation regarding vitamin K1 vs K2 intake. 

For adult men, the RDA is 120 micrograms (mcg) of vitamin K per day.  For adult women, the RDA is 90 mcg per day.  The RDA does not change in pregnancy or lactation. 

Indications for Vitamin K Supplementation  [4., 8., 13.]

Individuals interested in adding vitamin K supplements to their daily intake should consult with a licensed healthcare professional before initiating any new therapies.  

Vitamin K Deficiency

Although rare, Vitamin K deficiency can lead to serious health issues.  Symptoms of deficiency can include easy bruising, excessive bleeding from wounds or punctures, and heavy menstrual bleeding in women.

Populations at increased risk of vitamin K deficiency include newborns, individuals with certain digestive disorders affecting nutrient absorption, and those on long-term antibiotics are more susceptible to Vitamin K deficiency.

Blood Clotting Disorders

Vitamin K is crucial for synthesizing clotting factors, which are proteins necessary for blood coagulation.

Bone Health

Vitamin K plays a key role in bone metabolism by aiding in the carboxylation of certain bone proteins; this contributes to bone formation and maintenance and reduces the risk of osteoporosis.

Cardiovascular Health

This benefit is particularly associated with Vitamin K2, which helps prevent the calcification of arteries and other soft tissues.

Prevention and Treatment of Bleeding Disorders

Adequate Vitamin K levels are essential for normal blood clotting, preventing conditions like hemorrhagic disease, particularly in newborns.

Balancing Vitamin K Intake with Anticoagulant Therapies

Particularly for individuals on anticoagulant medications like warfarin, balancing Vitamin K intake is important to avoid interfering with the medication's effectiveness. Consistent dietary intake of Vitamin K2 helps in managing its levels.

Individuals on anticoagulant medications should speak with their healthcare provider regarding an appropriate intake of vitamin K, particularly vitamin K1 from vegetables.  

Lab Testing for Vitamin K2

Measuring Vitamin K2 levels in the body requires testing vitamin K levels, generally.  Alternatively, assessing clotting function may be appropriate.  

Methods of Vitamin K Testing

Vitamin K levels are usually measured through blood tests in serum and plasma. [13.]

However, direct measurement of Vitamin K in the blood is controversial.  [1., 3.]

Instead, some experts recommend indirect testing that assess blood clotting:

Prothrombin Time (PT) Test and PTT Test: these tests measure how long it takes for blood to clot. Since Vitamin K is vital for clotting, prolonged clotting time can suggest a deficiency.

Some experts note that urinary metabolites of vitamin K may be an alternative method of testing.  [1.]

Interpreting Vitamin K Test Results

Reference ranges can vary depending on the lab used; therefore it is important to contact the laboratory used to determine reference ranges.  

Reference ranges for vitamin K testing in the serum are often given as 0.2-3.2 ng/mL, although  impaired blood clotting has been associated with levels below 0.5 ng/mL.  [18.]

Factors Influencing Vitamin K Levels

Several factors can affect Vitamin K levels and/or function in the body:

Dietary Intake: the amount and type of Vitamin K-rich foods consumed significantly influence blood levels.

Gut Health: conditions affecting gut health, such as celiac disease or Crohn’s disease, can impair Vitamin K absorption.

Medications: certain medications like antibiotics and anticoagulants, can affect Vitamin K metabolism.  Specifically, broad-spectrum antibiotics can deplete the bacteria that produce vitamin K, while cephalosporins can inhibit vitamin K function.  [12.]  Anticoagulants impair vitamin K function.  

The Clinical Importance of Vitamin K Testing

Regular testing of Vitamin K levels is important in certain situations:

Identifying Deficiencies: early detection of low Vitamin K levels is crucial, especially in populations at risk, like newborns and individuals with malabsorption disorders.

Guiding Treatment: in cases of bleeding disorders or osteoporosis, Vitamin K testing can inform treatment strategies.

‍Monitoring for Medication Interactions: for individuals on anticoagulant therapy, monitoring Vitamin K levels may be important.

Related Biomarkers and Their Testing

To fully understand the function of Vitamin K in the body, considering related biomarkers may provide insight.

Biomarkers Associated with Vitamin K

The effectiveness and activity of Vitamin K in the body are closely related to several other health markers:

• Vitamin D: vitamin D and Vitamin K work synergistically in bone health and calcium metabolism, making it important to assess Vitamin D levels when assessing bone health.

• Prothrombin time test with an INR (PT/INR): the prothrombin time test with an international normalized ratio (PT/INR) is a laboratory test used to assess the blood's ability to clot by measuring the time it takes for blood to clot, normalized to a standard scale, to monitor and evaluate coagulation status and the effectiveness of anticoagulant therapy.  PT monitors the extrinsic clotting pathway.  

• Partial Thromboplastin time (PTT): the partial thromboplastin time (PTT) test is a laboratory assay used to evaluate the intrinsic pathway of coagulation, measuring the time it takes for blood to clot when specific reagents are added. It is often employed to assess the function of factors involved in the clotting cascade and to monitor patients on heparin therapy.

Diet and Lifestyle Measures to Optimize Vitamin K Levels and Function

• Incorporate vitamin K-rich foods into your diet, such as leafy greens (e.g., kale, spinach, Swiss chard), broccoli, Brussels sprouts, and parsley.  [10.]  Individuals on anticoagulant medications should speak to their doctor before adjusting their dietary intake of these vegetables. 

• Consume fermented foods like natto, sauerkraut, and kefir, which contain vitamin K2-producing bacteria.  [14.]

• Include healthy fats in your diet, as vitamin K is fat-soluble and requires dietary fats for absorption. Examples include olive oil, avocado, nuts, and seeds.

• Avoid excessive alcohol consumption, as it may impair vitamin K absorption and utilization.  [7.]

• Engage in regular physical activity, which supports overall metabolic health and may indirectly enhance vitamin K function.

• Practice stress management techniques, as chronic stress can negatively impact nutrient absorption and utilization and affect vitamin K-dependent proteins and is associated with increased oxidative stress and depression.  [19.]

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