|Grade||Level of Evidence|
|A||Multiple double-blind, controlled clinical trials.|
|B||1 double-blind, controlled clinical trial.|
|C||At least 1 controlled or comparative clinical trial.|
|D||Uncontrolled, observational, animal or in-vitro studies only.|
|Grade||Effect||Size of Effect||Comments|
Speeds up the resolution of bruises caused by laser treatment.
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Table of contents:
Vitamin K is the name for a group of lipophilic vitamins that function as essential co-factors for the synthesis of several proteins. In humans, they play important roles in blood clotting, bone health and cardiovascular health. The 3 major forms of vitamin K are vitamin K1, K2, and K3.
Vitamin K1, also known as phylloquinone or phytonadione, is present in all photosynthetic plants, algae and cyanobacteria, where it serves as the secondary electron acceptor in photosystem I. As a result, it is widely distributed in green vegetables including spinach, broccoli, cabbage and lettuce, plant oils including soybean, canola, cottonseed and olive, and vegetable oil products such as margarine, spreads and salad dressings.
Vitamin K2, the menaquinones, are primarily produced by intestinal bacteria or converted from vitamin K1 and/or vitamin K3. In the diet, they are found in meat, dairy products such as milk, eggs and cheese, and fermented foods such as the traditional Japanese soybean-based product called natto.
2.1 Oral administration
In the intestine, dietary vitamin K is incorporated into mixed micelles, which are taken up by intestinal enterocytes of the small intestine and incorporated into nascent chylomicrons. The chylomicrons then are secreted into the lymph and eventually enter the bloodstream.
Food composition affects the bioavailability of vitamin K. The bioavailability of vitamin K1 after consumption of spinach, broccoli or romaine lettuce was several times lower than that of an oral supplement, and vitamin K1 in the oil phase of meals also led to significantly greater bioavailability of vitamin K1 compared to vitamin K in a vegetable matrix.
Yet, even after accounting for the effects of food matrices, there is still a large variation among individuals in vitamin K1 bioavailability, indicating the presence of non-dietary factors. Bioavailability of vitamin K1 from kale ranged from 1-14%, for instance.
There is little information on the bioavailability of vitamin K2 from dietary sources or from intestinal microflora. A comparative study showed that peak plasma concentrations of menaquinone-4 and menaquinone-9 were < 20% of that for vitamin K1, possibly due to a faster absorption and clearance for menaquinone-4 and a less efficient absorption for menaquinone-9. Vitamin K2 produced by intestinal bacteria is believed to contribute to vitamin K nutrition, but to a much smaller degree than previously thought.
Whether dietary vitamin K increases the levels of vitamin K in the skin is not known.
2.2 Topical administration
The skin penetration of vitamin K has been assessed using pig ear skin. Vitamin K is lipophilic, and 2.5% vitamin K in a lipophilic vehicle (liquid petrolatum) delivered vitamin K mainly to the stratum corneum with low penetration in the viable epidermis, presumably due to an accumulation in the stratum corneum. The same concentration of vitamin K formulated in a monoolein-based hexagonal phase gel or nanodispersion however, delivered approximately 2x more vitamin K to the stratum corneum and 2-4x more vitamin K to the epidermis and dermis, which may be attributable to the action of monoolein as a penetration enhancer.
Nanoencapsulation of vitamin K1 in lipid-core nanocapsules has also been shown to increase vitamin K1 retention in the outermost skin layer, raise the amount of vitamin K1 in the dermis and decrease the permeation of vitamin K1 through the skin.
3. Effects on the skin
3.1 Lightening effect
A few studies have investigated the effectiveness of vitamin K and retinol in improving periorbital hyperpigmentation. In 1999, an uncontrolled study showed that the use of topical 1% vitamin K + 0.15% retinol improved dark circles in 26 out of 28 patients based on investigator evaluations and patient self-evaluations. Another study published 2 years later found that significant improvements in dark circles were seen in patients treated with products containing vitamin K and retinol, compared to patients who used only sunscreen.
In 2004, an open-label study enrolled 57 Japanese adults with dark under-eye circles and wrinkles to determine the effects of a gel containing 2% vitamin K1, 0.1% retinol and 0.1% vitamin C + vitamin E. Twice daily application of the gel formulation to the lower eyelid for 8 weeks decreased haemostasis in 47% of patients, and also reduced wrinkles in some patients, but did not clearly remove pigmentation, leading to the conclusion that the gel was fairly or moderately effective in reducing dark under-eye circles, especially in cases where the under-eye circles are caused by haemostasis.
It has been hypothesized that vitamin K may decrease the visibility of the capillary bed under the eye, and that retinol may accelerate the removal of melanin granules from the under-eye area. However, the lack of a controlled study comparing the effects of vitamin K alone versus placebo makes it impossible to ascertain its individual lightening effect.
3.2 Faster resolution of bruises
Cosmetic procedures such as pulsed dye laser treatment and blepharoplasty can result in significant bruising that takes time to resolve. These bruises can be eliminated or their durations shortened by topical application of vitamin K.
The first study using vitamin K on bruises was published in 1995. Blood was injected into both forearms of 6 patients to produce bruising, following which one arm received 1% vitamin K cream application twice daily and the other arm was left untreated. Bruises were noted to clear in 5-8 days when the vitamin K cream was used, whereas they took 11-13 days without treatment, leading to the conclusion that vitamin K may induce the disappearance of extravascular blood. A second trial reported in the same paper had 12 patients with actinic purpura apply 1% vitamin K cream to one forearm and placebo to the other in a double-blinded manner. The time required for healing using the vitamin K cream was 2-3 days, compared to 7-9 days for the placebo. However, the method of assessment was not specified, raising questions as to why the results were given in days when patients were seen only at 2-, 4- and 6-week intervals. 
On the basis of these observations, a larger study on 20 patients was conducted and published in 1999 that tested multiple formulations of vitamin K on laser-induced bruising. Each subject had a control site that was untreated and 4 other sites where different formulations were applied 2 weeks before and 2 weeks after laser treatment. The formulations tested included 3% and 5% vitamin K, 1% vitamin K + 0.3% retinol, and 1% free vitamin K cream. Of these, the combination of 1% vitamin K + 0.3% retinol was shown to more quickly clear the purpura.
This finding was replicated in another double-blind and placebo-controlled trial, where a 5% vitamin K cream was also found to reduce the severity of bruising compared to a placebo when applied for 2 weeks after laser treatment, especially in the initial 10 days of application.
In addition, a cream containing vitamin K oxide was revealed to help resolve bruises induced by pulsed dye laser treatment in subjects being treated for bilateral facial telangiectasia in another double-blind, placebo-controlled and split-face study.
On the other hand, topical 0.5% vitamin K was not effective on bruises caused by mechanical injury, though this may be due to the very low concentration of vitamin K in the formulation.
Yet another study found that neither a 5% vitamin K ointment nor a 1% vitamin + 0.3 retinol ointment differed significantly from placebo (white petrolatum) in anti-bruising activity. However, because the 5% vitamin K formulation was not inferior to a 20% arnica ointment that was superior to placebo, it was thought that a larger study may be able to prove the clinical relevance of 5% vitamin K.
3.3 Prevention of rash
The use of EGFR inhibitors such as cetuximab in targeted oncology therapy can result in skin toxicities, the most common of which is acneiform rash. Vitamin K1 applied topically may help to prevent or treat cetuximab-induced skin rash, though the evidence is limited and sometimes contradictory.
A skin cream containing urea and 0.1% vitamin K1 (Reconval K1) improved rashes after 18 days in a study of 30 patients with metastatic colorectal cancer who were undergoing treatment with cetuximab in combination with chemotherapy, and was also thought to have potential for prophylactic use. 2 other studies, including a pilot clinical trial, also indicate that pre-treatment with vitamin K1 cream may have a possible benefit as prophylaxis for cetuximab-induced skin rash in metastatic colorectal cancer. However, an interventional study using a historical control found that pre-treatment with topical vitamin K1 cream did not translate into clinically meaningful benefit in terms of decreasing the risk of acneiform rash in metastatic colorectal cancer patients treated with cetuximab.
4. Side Effects
There have been several case reports of contact allergy or contact dermatitis to vitamin K in cosmetic products, including Ureadín Facial Eye Contour, Auriderm K2, Auriderm K5, eye creams and a clarifying cream.
Vitamin K1 was banned from cosmetic products by the French health regulator in 2006 due to its sensitizing properties and concerns that individuals affected by such an allergy could not be medicated with vitamin K1 if needed in the event of a medical emergency. The European Commission's Scientific Committee on Consumer Safety followed suit in 2010, issuing its opinion that vitamin K1 is not safe when used in cosmetic products at concentrations up to 1% for the same reasons.
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