Vitamins E and K: their role and the effects of deficiency

Introduction

In this fourth article in our series on vitamins and minerals, we conclude our review of the major vitamins by examining the nature and physiological functions of the fat-soluble vitamins E and K. We also review current evidence linking deficiencies of these vitamins with various pathological states.

Vitamin E

Vitamin E is the collective name for a group of eight structurally related, fat-soluble molecules. Humans cannot synthesise these vitamin E molecules; they are primarily manufactured by plants and algae so are designated as essential vitamins that must be obtained through the diet (Zingg, 2019).

This group of vitamin E molecules include four tocopherols and four tocotrienols. The molecule alpha-tocopherol (Fig 1) is the major form found circulating in the plasma (Péter et al, 2015) and, in humans, is responsible for around 90% of collective vitamin E activity (Ungurianu et al, 2022). Due to its abundance and high biological activity, alpha-tocopherol is commonly referred to as vitamin E, with the two terms frequently used interchangeably (Muthulakshmi et al, 2023).

Sources and recommended doses

Good sources of vitamin E include:

• Nuts and seeds;
• Plant oils including olive, rapeseed, sunflower and corn oils;
• Wheatgerm, found in cereal-rich foods.

Currently the NHS recommends a daily intake of 4mg per day for men and 3mg per day for women (NHS, 2020a), which can easily be achieved with a well-balanced diet. However, doses of up to 540mg per day are regarded as safe and unlikely to cause problems, as any excess vitamin E not used by the body can be stored in the liver and fat reserves for subsequent use (NHS, 2020a).

Absorption and transport

It is estimated that 20-80% of vitamin E consumed is absorbed in the gut (Schmölz et al, 2016). Unlike vitamin D – as discussed in the previous article in this series – no binding protein for vitamin E has been identified. Like cholesterol, vitamin E is transported in association with lipoprotein molecules, which act as transport vehicles (Schmölz et al, 2016).

Deficiency of vitamin E is rare with a balanced diet and is most likely to occur in individuals with problems digesting and absorbing fat. Weight-loss drugs such as orlistat, which limit fat absorption in the gut, can significantly reduce absorption of vitamin E and other fat-soluble vitamins, potentially leading to deficiency. For this reason, patients prescribed orlistat are often advised to take multivitamin supplements containing the key fat-soluble vitamins. This ensures that despite reduced absorption, a healthy concentration in the plasma can be maintained (Bansal and Al Khalili, 2022; McDuffie et al, 2022).

Vitamin E homeostasis

In the liver cells (hepatocytes), a highly specific transfer protein called alpha-tocopherol transfer protein (alpha-TTP) binds to vitamin E with high affinity, allowing a reservoir of vitamin E to form within the liver (Arai and Kono, 2021). Alpha-TTP also serves to protect vitamin E from enzymatic degradation within the liver. Vitamin E can detach from alpha-TTP and then be released gradually from the liver into the blood to maintain normal plasma concentrations (Schmölz et al, 2016). Alpha-TTP has also been found in smaller amounts in other organs, including the spleen, brain, retina, kidney, lung and uterus. It has been suggested that these regions may be particularly susceptible to vitamin E deficiency, and the presence of this high-affinity binding protein allows a pool of vitamin E to be preferentially stored in these tissues (Arai and Kono, 2021).

The optimal plasma concentration of vitamin E is at least 12 μmol/L, but higher levels of around 30 μmol/L have been recommended to improve cardiovascular health (Rychter et al, 2022). Currently many countries recommend levels of 30 μmol/L or over as being generally beneficial to human health (Péter et al, 2015).

Free vitamin E will circulate in the plasma and diffuse into cells to exert its effects. The liver is particularly important for preventing excess, and potentially toxic, build-up of vitamin E. Within the hepatocytes, vitamin E binds to the pregnane X receptor, which enhances the production of the cytochrome P450 enzymes CYP3A and CYP4F2; these degrade vitamin E into water-soluble metabolites that can be freely eliminated in the urine (Zingg, 2019).

Physiological roles

As an antioxidant
Vitamin E plays a vital role in protecting phospholipid molecules that are the major components of cell (plasma) membranes. Cells are continually exposed to damaging free radicals, which are highly reactive atoms, molecules or ions that have at least one unpaired electron. Free radicals are generated via normal metabolic processes by leukocytes (white blood cells) when they kill pathogens, or when the body is exposed to certain environmental factors, including ionising radiation, cigarette smoke and other pollutants.

Being highly reactive, free radicals have the potential to inflict considerable damage through oxidative stress (Jomova et al, 2023); they can significantly disrupt the integrity of cell membranes and potentially lead to cell death (Liao et al, 2022). Like vitamin C (as discussed in the first article in this series) and vitamin K (see below), vitamin E is an antioxidant, which acts as a highly efficient free radical scavenger, binding to free radicals to prevent them from inflicting damage to cellular components. Once acquired through diet, vitamin E is incorporated in cell membranes, perfectly positioning it to scavenge and neutralise any damaging free radicals in the vicinity of the cell membrane (Fig 2).

As well as protecting the phospholipid molecules of cell membranes, vitamin E also protects lipoproteins (proteins with lipid molecules attached) and intracellular lipid droplets, which are stored pools of lipid held in many cell types (Liao et al, 2022).

Immune function
Vitamin E is a known immune modulator and is regarded as acting as a general anti-inflammatory molecule. Research has shown that older people given a daily supplement of 200mg of vitamin E display enhanced immune responses (Muthulakshmi et al, 2023).

Cardiovascular health
Vitamin E is regarded as being beneficial to cardiac health, with an important role in helping prevent cardiovascular disease, particularly coronary artery disease and other forms of atherosclerotic (thickening or hardening of the arteries by fatty deposits) occlusion. However, aside from its well-documented antioxidant effects, the role played by vitamin E in cardiovascular disease remains poorly understood, with many studies being small scale and often contradictory (Rychter et al, 2022).

Type 2 diabetes
The potential role of vitamin E supplementation in diabetes mellitus has been examined in multiple studies, with some showing beneficial effects, others worsening of disease and some no effect at all. The most recent meta-analysis assessed the outcomes of 38 randomised controlled trials to examine the effects of vitamin E on glycaemic control and insulin resistance (Asbaghi et al, 2023). This study found supplementation caused significant reductions in glycated haemoglobin (HbA1c) scores (a measure of long-term glucose control) and fasting insulin levels. It also demonstrated that short-term interventions with vitamin E led to reduced fasting blood glucose concentrations. Although not conclusive, this study seems to indicate that vitamin E may be useful in helping manage type 2 diabetes.

Neurological health
Vitamin E supplementation is thought to play a beneficial role in many neurological diseases, including epilepsy, Parkinson’s disease and Alzheimer’s disease. Unfortunately, many studies have been small-scale and yielded contradictory results, which means much larger randomised controlled trials are required (Muthulakshmi et al, 2023).

Deficiency of vitamin E can be caused by mutations in the alpha-TTP gene, which codes for the alpha-TTP that regulates plasma levels of vitamin E. Significantly low levels of available vitamin E can trigger damage to the brain and spinal cord, causing a condition called ataxia with vitamin E deficiency (AVED). This neurodegenerative disease is characterised by impaired movement and coordination. It is also associated with loss of sensation in the limbs (peripheral neuropathy), reduced leg reflexes and speech problems (dysarthria).

Other areas of the body that can also be affected by AVED include the spine (abnormal curvatures or scoliosis), the heart (cardiomyopathies) and the eyes (leading to retinitis pigmentosa, which significantly impairs vision).

Once diagnosed, AVED can be successfully treated by lifelong supplementation of vitamin E (National Organisation for Rare Diseases, 2023).

Vitamin K

As with vitamin E, vitamin K is the collective term for a group of structurally related fat-soluble vitamins. Two major forms (isomers) are particularly important to human physiology (Fig 3).

Vitamin K1

Vitamin K1 (phylloquinone) is acquired predominantly through the diet, with green leafy vegetables including cabbage, broccoli, Brussels sprouts and lettuce, accounting for an estimated 40-50% of total intake (Rajagopal et al, 2022). Other good sources include tomatoes, vegetable oils (such as sunflower, olive and canola) and some fruits (such as kiwi, avocado, blueberries, pomegranates, green grapes and figs) (Rajagopal et al, 2022).

Vitamin K2

Vitamin K2 (menaquinones) can also be obtained through the diet, being found in fermented foods, meats and dairy products (Rajagopal et al, 2022), with meats, cheeses and egg yolks major dietary sources in European populations (Haugsgjerd et al, 2020). Vitamin K2 can also be synthesised by resident bacteria in the gut. Among the complex community of bacteria making up the gut microbiota are various groups of vitamin K2-synthesising bacteria; these include firmicutes, proteobacteria, and bacteroidetes. Currently the Human Microbiome Project has identified through genetic sequencing 34 types of intestinal bacteria with the necessary enzymes to synthesise vitamin K2 (Yan et al, 2022). Vitamin K2 is more biologically active and has a longer half-life (days rather than hours) than K1 (van Ballegooijen and Beulens, 2017).

It is estimated that humans require 1µg of dietary vitamin K per 1kg of body weight per day, so a person weighing 80kg (around 176lbs) would require 80µg (NHS, 2020b).

“Vitamin K is essential for normal blood clotting”

Absorption and transport

Dietary-acquired vitamin K1 and K2 are absorbed in the small intestine and, as with vitamin E, transported in association with lipoprotein molecules. Research indicates that absorption of bacterially synthesised vitamin K2 across the colon is poor (Liu et al, 2019). Despite this, it is believed vitamin K of bacterial origin still satisfies some of the body’s requirement for vitamin K (National Institutes of Health (NIH), 2021).

Vitamin K is initially transported to the liver, which acts as a storage reservoir. Here it forms a complex with a liver protein (apolipoprotein B-100), which can be released back into the circulation as part of low-density lipoprotein (LDL) micro-particles. Circulating LDL containing vitamin K maintains the plasma vitamin K concentration and can act on target organs and tissues, including the brain, cartilage, bone heart and arteries, which have LDL receptors (Cemortan and Cernetchi, 2021). Plasma levels of vitamin K are much lower than those of many other vitamins. There is much variation in the recommended normal plasma ranges, although a reference range of 0.2-3.2 ng/ml is typically quoted (Kraemer, 2022).

Physiological roles

Coagulation
Vitamin K is essential for normal blood clotting. Both forms (K1 and K2) act as cofactors for the enzyme vitamin K-dependent carboxylase (VKDC). VKDC is vital for the synthesis of many protein factors involved in the blood clotting cascade (NIH, 2021); these include factors II (prothrombin), VII, IX and X (Rajagopal et al, 2022). VKDC converts the glutamate residues (amino acids) of these proteins into gamma carboxyglutamate (Gla) residues; this is necessary for their normal functioning within the clotting cascade (Rajagopal et al, 2022). Reduced synthesis of functional clotting factors can significantly reduce the blood’s ability to clot, increasing the risk of haemorrhage, with reduced levels of vitamin K below 0.5 ng/ml associated with impaired clotting (Kraemer, 2022).

Anticoagulation therapies
Many medications prescribed to prevent clots forming (for example, in conditions such as persistent atrial fibrillation) act to antagonise vitamin K; these include warfarin and many other common anticoagulants used in European countries (NIH, 2021). By antagonising the effects of vitamin K, such medications reduce the concentration of active clotting factors, decreasing the likelihood of thrombosis.

Patients taking drugs such as warfarin must avoid eating excessive amounts of vitamin K-rich foods and supplements containing vitamin K, as this can increase the risk of clots (Fig 4). Conversely, vitamin K intake must be adequately maintained, as low levels can increase the risk of bleeding (Fig 4). The NHS recommends ideally keeping the diet stable to prevent fluctuations in vitamin K levels and avoid the need to continually adjust the warfarin dose (NHS, 2022a). Interestingly, high doses of vitamin K are usually part of the treatment regime for patients who have suffered a warfarin overdose (Deaton and Nappe, 2023).

Skeletal effects
As highlighted above, vitamin K is a cofactor for VKDC. In addition to its role in producing clotting factors, VKDC is involved in bone health, being essential for the synthesis of several key bone proteins, including osteocalcin, matrix Gla protein (MGP), Gla-rich protein, protein S and growth arrest-specific 6 protein (Fusaro et al, 2020). Of these, osteocalcin is the best studied, being the tenth-most abundant protein in the human body, produced by the bone-forming cells (osteoblasts). When acted upon by VKDC, the glutamate residues in osteocalcin are converted into Gla residues and osteocalcin develops a strong affinity for calcium and phosphate ions (Karsenty, 2023). These form the major mineral component of bones, imparting essential hardness and rigidity to their structure (Knight et al, 2020).

For many years osteocalcin was thought to be a major factor in maintaining bone density, but recent research indicates it only has a minor effect (Moser and van der Eerden, 2018). Indeed, bone density in genetically modified experimental animals that no longer produce osteocalcin is barely affected (Karsenty, 2023). However, osteocalcin is involved in the correct alignment of calcium phosphate (hydroxyapatite) crystals between the collagen fibres of bone, which is thought to enhance bone quality (Alonso et al, 2023), increase bone strength and potentially reduce fracture risk (Mladenka et al, 2021).

Over the years, there has been much interest in using vitamin K to improve bone health and reduce osteoporosis and fracture risk. Indeed, Japan and some other Asian countries use vitamin K as a treatment for osteoporosis. Additionally, the European Food Safety Authority approved a claim that “a cause and effect relationship has been established between the dietary intake of vitamin K and the maintenance of normal bone” (NIH, 2021). However, currently, the potential benefits of vitamin K supplementation for bone health remain unclear, with many studies reporting contradictory findings (NIH, 2021).

Recently, many research articles have highlighted that osteocalcin that has not been carboxylated by VKCD circulates in the blood in small amounts and functions as a hormone (Mladenka et al, 2021). In this role as an endocrine signal, osteocalcin has been demonstrated to influence a diverse range of human physiological processes, including metabolism, blood glucose homeostasis, synthesis of steroid hormones, cognition and memory (Karsenty, 2023).

“Although the evidence is variable, vitamin K appears to play a role in many other aspects of human physiology and pathology”

Antioxidant effects
Vitamin K can act as a potent scavenger of free radicals, with research indicating it has antioxidant activities that are 10-100 times greater than other radical scavengers, including vitamin E. It has been suggested that, like vitamin E, vitamin K plays an important role in protecting cell membranes from oxidative damage (Halder et al, 2019).

Cardiovascular health
VKDC is required for normal synthesis of MGP by the smooth muscle cells of blood vessels. As before, VKDC catalyses the conversion of glutamate residues (amino acids) of the initial protein into Gla residues. This form of MGP reportedly acts as the most powerful inhibitor of blood vessel calcification (Hariri et al, 2021). This helps to protect important vessels such as the coronary arteries, with low vitamin K levels associated with increased vessel calcification. Evidence is also emerging that a higher intake of vitamin K is associated with reduced risk of coronary artery disease (Haugsgjerd et al, 2020), reduced calcification of heart valves and reduced heart disease-associated mortality (Rajagopal et al, 2022).

Other suggested roles for vitamin K

Although the evidence is variable, vitamin K appears to play a role in many other aspects of human physiology and pathology. A review by Schwalfenberg (2017) highlighted that normal or elevated levels of vitamin K have been associated with:

• Helping prevent disabling osteoarthritis;
• Reduced formation of calcium oxalate kidney stones;
• Decreased risk of developing diabetes;
• Improved glycaemic control;
• Improved parameters in many cancers, including lung, prostate, pancreatic and hepatic;
• Improved cognition in older people, with the same review highlighting that patients with Alzheimer’s disease often had lower vitamin K intakes.

Vitamin K deficiency and toxicity

Vitamin K is continually recycled within cells, so deficiency in adults is rare. However, as with vitamin E deficiency, vitamin K deficiency is occasionally seen in patients with malabsorption disorders or those taking drugs such as orlistat, which block fat absorption. Deficiency is more common in newborns and early infancy because of poor placental transfer from the maternal blood and the low vitamin K content of breast milk. This can lead to vitamin K deficiency bleeding, which is associated with bleeding in the newborn from the skin, nose, umbilicus and other sites (NIH, 2021). In the UK, parents are offered a vitamin K injection for their newborns or, if they prefer, an oral solution (NHS, 2022b).

There have been virtually no reports of toxicity associated with overconsumption of vitamin K in humans or animals (Mladenka et al, 2021). However, as previously noted, high levels of vitamin K can significantly impair some anticoagulant therapies.

Conclusion

Within this series on vitamins and minerals, this article has concluded our review of the major vitamins by examining the nature and physiological functions of vitamins E and K. We have also highlighted current evidence linking deficiencies of these vitamins with various pathological states.

• The next article in the series examines the physiological roles of the minerals calcium, phosphate, iron, sodium and potassium.

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