1. Introduction

2. Vitamin K biology and the visual system

2.1. Vitamin K content and deliver to ocular and related tissue

Only one study reports the tissue concentration of PK and MK4 in the eyes of female and male mice [39]. The remainder of the data must be extrapolated from reports of PK and MK content and distribution in human brains, as well as animal brain studies, or gleaned from analyses of associated factors in human and bovine vitreous and aqueous humor. Studies related to the delivery of other nutrients to the eye and brain via LDL and HDL also exist. 

In their 2008 foundational work, Okano and co-works [39] using deuterium labeling, provided unequivocal evidence that MK4-d7 in the mouse cerebrum originates from dietary PK-d₇ and/or MD-d₈ by one of two routes, either by the conversion of PK to MD in the intestines followed by MD uptake and conversion to MK4 in the  cerebrum, or uniquely, the first evidence of tissue specific,  PK>MD>MK4 conversion within the brain. They conclude that their data suggests that the cerebrum is particularly unique as it contained relatively large amounts of MK4 but little to no PK, likely the result of the blood brain barrier (BBB) or other unknown mechanisms [39]. They also provided valuable oral PK>MD>MK4 kinetic data showing in female mice, PK-d₇ and MK-d₈ were converted into cerebral MK4-d₇ over 24 hours in a dose-dependent fashion from a physiological dose of 0.1 μmol/kg body weight to what was considered a pharmacological dose of 10 μmol/kg body weight. Additional they showed that a single oral administration of PK- d₇ at 10 μmol/kg body weight resulted in the accumulation of MK-4- d₇ in the cerebra at a concentration of 82.9 ± 6.1 pmol/g tissue, nearly 30% of the concentrations (252.5 ± 10.3) of MK-4 in the cerebra of age-matched female mice within 24 hours [39].This conversion of PK to MD had long been understood to occur but was not previously proven. Many aspects of this pathway remain important open questions.   

Table 1 of their work is reproduced below and appears to be the only source of detailed information with respect to VK levels in the eyes and 27 other tissues of mice. It can be readily seen that there is marked variability in PK and MK4 concentrations among tissue types and even within different regions of the brain, which is in concert with MK/PK concentration data reported in nine separate areas of the rat brain but without eye associated information reported previously by Ferland in 2004 [40]. 

Figure 1 is a graph of the tissue distribution of vitamin K (pmol/g) in mice fed a normal diet sorted with respect to female MK4 concentrations.

Table 1. Tissue distribution of vitamin K (pmol/g) in mice fed a normal diet.

Table 1. Tissue distribution of vitamin K (pmol/g) in mice fed a normal diet.

Adapted from: Okano, T.; Shimomura, Y.; Yamane, M.; Suhara, Y.; Kamao, M.; Sugiura, M.; Nakagawa, K. Conversion of Phylloquinone (Vitamin K1) into Menaquinone-4 (Vitamin K2) in Mice: Two Possible Routes for Menaquinone-4 Accumulation in Cerebra of Mice. J Biol Chem 2008, 283, 11270–11279, doi:10.1074/jbc.M702971200. [39] CC BY license.

Figure 1. Mean (n=5) tissue MK4 and PK concentration (pmol/g) in mice fed a normal diet sorted by female MK4 concentration. Red color denotes female MK4, Green-Female PK, Orange-male MK4, and Blue-male PK. Note tissue type, gender, female:male MK and PK ratios as well as tissue type and gender MK:PK ratios. (Adapted from: Okano, T.; Shimomura, Y.; Yamane, M.; Suhara, Y.; Kamao, M.; Sugiura, M.; Nakagawa, K. Conversion of Phylloquinone (Vitamin K1) into Menaquinone-4 (Vitamin K2) in Mice: Two Possible Routes for Menaquinone-4 Accumulation in Cerebra of Mice. J Biol Chem 2008, 283, 11270–11279, doi:10.1074/jbc.M702971200. [39] CC BY license).

Figure 1. Mean (n=5) tissue MK4 and PK concentration (pmol/g) in mice fed a normal diet sorted by female MK4 concentration. Red color denotes female MK4, Green-Female PK, Orange-male MK4, and Blue-male PK. Note tissue type, gender, female:male MK and PK ratios as well as tissue type and gender MK:PK ratios. (Adapted from: Okano, T.; Shimomura, Y.; Yamane, M.; Suhara, Y.; Kamao, M.; Sugiura, M.; Nakagawa, K. Conversion of Phylloquinone (Vitamin K1) into Menaquinone-4 (Vitamin K2) in Mice: Two Possible Routes for Menaquinone-4 Accumulation in Cerebra of Mice. J Biol Chem 2008, 283, 11270–11279, doi:10.1074/jbc.M702971200. [39] CC BY license).

Importantly, the eye was found to contain both PK and MK4 with a MK4/PK ratio of 6.75 and 5.63 in females and males respectively. PK and MK4 values are consistently higher in females with a ratio of 1.49 for PK and 1.78 for MK4 in the eye. The eye appears to be enriched with respect to PK compared to the cerebrum and to be reduced in MK-4 with ratios of 0.41 and 0.55 in females and males respectively. PK values would appear less certain given smaller concentrations and larger SE values. Caution should be taken in drawing too many conclusions from this preliminary ocular data as the primary purpose of the study was to understand the generation of MK4 within the mouse cerebrum. The eye, in part an embryologic extension of the brain, is however much less homogeneous than the brain, containing many different tissue types, including a large volume of vitreous humor which is 99% water, thus giving rational for the undertaking of an aggressive program to map tissue specific MK4 (and possible other MKn) and PK concentration of the human eye.

Building upon their work, Nakagawa, Hirota, and colleagues in 2013 [41] demonstrated unequivocally using deuterium-labeled PK (PK-d₇), that tissue MK4 in rats is primarily derived from dietary PK that is converted to MD in the intestines and released into the general circulation by way of the lymphatic and circulatory systems. They further demonstrated a similar time course change in PK, MK4, and MD concentrations in healthy adult volunteers that they believed provided evidence of similar action in humans. Their kinetic data suggested that the bulk of the PK was absorbed in the intestine and passed unaltered via the mesenteric circulation to the liver, but that a smaller, yet critical amount of PK, was converted to both MD and MK4 in the intestines and entered the mesenteric lymphatics. The lymph concentrations of PK-d₇ were approximately 50-fold higher than those of MD-d₇ and 1,000-fold higher than those of MK4-d_7. They maintain that their tissue concentration data, along with their previous work [39], indicates that PK is mainly stored in the liver, and that the cerebrum actively accumulates MK4 in rats and mice, with mice accumulations being higher than rats. Unfortunately, no ocular data was provided in this work.

The authors comment that their results are in concert with Thijssen et al. 2006 [42] who found that approximately 5-20% of an oral dose of PK in healthy male volunteers was catabolized to MD, and that unsupplemented subjects had a daily excretion of MD in the urine of 1.6-9.1 μg. The implication for the eye and brain are clear, as both Nakagawa and Thijssen note, that the smaller lipophilic MD can more easily pass the blood-brain barrier (BBB), and by extension, the blood-retinal barrier (BRB), to supply intracellular MK4 upon conversion.  Partridge 1998 [43] and Vita et al. 2011[44] detail that lipid-soluble molecules with a mass under 400-600 Da are transported readily by lipid mediated free diffusion through the vascular endothelial plasma membranes and are desirable for central nervous system drug deliver, which may indicate that MK is able to rapidly and passively enter the circulation after conversion in the enterocytes. The molecular weight of MD is 172.2 Da, and by contrast-MK4 is 444.6, PK is 450.07, MK7 is 649.0, MK9 is 785.23, and MK13 1057.7. It is important to note that this property of MD may be a two-edged sword, in that the use of MD as a pharmacologic agent to treat VK deficiency was stopped long ago, as it caused hemolytic anemia, and liver damage [21], but it is now being used in small titrated doses along with high dose vitamin C to treat glioblastoma [44]. Thus, there appears to be a very elegant sorting mechanism by which abundant PK, and possibly all MK_n dietary forms, as recently demonstrated by Ellis et al. 2021[45], are converted to the smaller more lipid soluble MD in a titrated manner to facilitate delivery to the brain and eye, while larger forms are packaged into chylomicrons, LDL, and HDL, for export via the vascular circulation to the liver, pancreas, kidney, bones, eye, brain, and other sites.

With respect to human studies, Thijssen et al. 1996 [46] report on six autopsy cases of which three contributed brain tissue.  PK was found in all tissues type with relatively small amounts in the brains with a median and (SD) of 1.5 (0.7) pmol/g. MK4 levels were relatively high in the brain, with a median of 6.3 (2.8) pmol/g. MK4 exceeded PK levels only in the brain and kidney. The MK4/PK ratios in the brains were 2.4, 3.4, and 13.3. with a mean of 6.4 (6.0) (not unlike the MK4/PK ratios of 5.63-6.75 reported by Okano in 2008 in mice eyes). In contrast, the livers were found to have total VK stores ranging between 40-125 pmol/g wet weight with PK ranging from 4-45% of the total. Thus, both PK and MK were consistently found in the human brain.

Tanprasertsu et al. in 2021 [47] reported on the MK4 and PK levels in the frontal and temporal cortex of 45 decedent centenarians in the Georgia Centenarian Study with and without dementia.  The overall mean and (SD) concentrations for MK4 were 4.96 (2.32) and 0.40 (0.39) pmol/g for PK, which were not significantly different between those with and without dementia. Of interest and potential significance, all brains were found to contain MK4, but in 38% no PK was detected. The MK4/PK ratio was 12.4 among all subjects which is within the range reported by Thijssen. Interestingly, in a companion paper reporting on the same individuals [48], brain retinol mean pmol/g and (SD) levels were 691.97 (305.56) and α-tocopherol mean pmol/g and (SD) levels were 66,917 (13,676). The ratios of retinol to MK4 and PK were thus 140 and 1730 respectfully, and that to α-tocopherol were 13,491 and 167,293, both highlighting and reaffirming the low relative tissue levels of VK compared to other fat-soluble vitamins[19].

Further brain VK data was found in a retrospective analysis of frozen brain tissue. Fu et al. 2021[49] report on 499 participants in the Rush Memory and Aging Project (mean age 92 y, 72% female) and found the MK4 levels in brain tissue stored from 0.4 to 13.0 years was 1.2 pmol/g, which they note is much lower than others have found.  PK levels were reported as non-detectable, though small amounts were seen below levels able to be accurately reported.

In a recent major advance, Booth et al. in 2022 [50], reporting on a subset of the Rush Memory and Aging Project, presented data linking VK content in 325 human brains, for the first time, to post-mortem neuropathologic histology and cognitive function prior to death. Brain MK4, mean pmol/g and (SD), ranged from 1.51 (5.5), 0.73 (4.6), 1.61 (7.2) in the mid-frontal/mid-temporal cortex, anterior watershed area, and cerebellum respectfully. Brain MK4 concentrations were inversely correlated with Alzheimer’s disease (AD) global pathology, neurofibrillary tangle density, Braak stage, and Lewy body presence, all well-established markers of neurodegeneration, as well as positively correlated with higher cognitive function and a slower rate of cognitive decline prior to death. Both the neurodegenerative findings and cognitive decline have clear connections to visual function and clinically relevant anatomic correlates to ocular findings, which will be addressed subsequently. Of interest, average brain MK4 concentrations, which were very carefully assayed and validated, stood on the order of three to five times less than those reported by Tanprasertsu et al., and Thijssen et al., which may reflect differences in the way brains were handled and stored, as well as differences in assay protocols, or possibly, actual tissues variances among the populations.

Thus, the available data would suggest that MK and PK are consistently found in human, mouse, and rat brain tissue with MK4/PK ratios that vary, but that consistently favors MK4. Mouse evidence documents MK4 and PK in the eye with MK4/PK ratios of 6.75-5.63 in females and males respectfully. MK4 and PK levels in human eyes are currently unreported but should be able to be quickly confirmed. Further, a portion (possibly 5-20%) of dietary PK, MK4, and likely MK_n forms as well, are converted to MD in the intestines, passively absorbed into the circulation because of its small M.W (172.2 Da) and lipophilicity; key physicochemical properties determining absorption, distribution, metabolism, excretion, and toxicity (ADMET) of a compound [51]. MD may then rapidly cross the BBB and BRB to be taken up by the cells in the brain and eye and quickly converted to MK4. In addition to providing an elegant mechanism to overcome the important BBB and BRB, and likely optimize brain and ocular VK levels, this PK>MD>MK4 conversion has long suggested to experts[19,21,41,46,52], that MK4 likely has important intracellular functions in addition to carboxylation of VKDP’s.

Corollaries to the above discussion are the facts that 75% or more of the dietary PK and MK is not converted to MD, and that the conversion PK> MD>MK4 does not explain the mechanism for the accumulation of PK in the eye and brain. PK and MK, as lipophilic vitamins, along with cholesterol and carotenoids such as lutein and zeaxanthin , are insoluble non-swelling amphiphilic polar lipids, absorbed along with other dietary fats as has been expertly reviewed by Ji et al. in 2009 [53] and again by Shearer et al in 2012 [54], and more recently by Lai et al in 2022 [55]. Important with respect to the ocular system is the fact LDL and HDL each carry approximately 7% of serum associated PK [56], with LDL containing both MK4 and MK9 forms as well, while HDL was found to carry only MK4 [57], which may be particularly important with respect to MK4 preferential concentration in the eye and brain.

In the early 1980’s it was pointed out that lipids were present in human aqueous humor (AH) at a mean concentration of 16.4 mg/dl, with HDL felt likely to be the sole lipid transporting lipoprotein, at concentrations of 4 micrograms/ml. This suggested to the authors that HDL was transported into the anterior chamber via AH, and that HDL may be an important source of lipids to the lens and other anterior chamber tissues [58,59]. The near exclusive and relatively abundant presence of HDL related apoproteins in the AH, and only rare or absent LDL related ApoB lipoprotein, has been confirmed using state of the art liquid-chromatography mass spectrometry (LC-MS/MS) by two groups in 2009 and 2020 [60,61]. Further, Conner et al. 2007 [62] and Li et al. [63] have demonstrated the unique role HDL plays in delivery of carotenoids to the retinal pigment epithelium and retina, and likely by extension, MK4 as demonstrated by Schurgers and Vermeer 2002 [57]. Thus, the importance of HDL transporters in ocular VK biology are implicated.

Yamanashi et al. 2017 [64], have recently linked the intestinal absorption and export of dietary PK by enterocytes to membrane proteins previously known to be essential in cholesterol metabolism, including Niemann-Pick C1 like 1 (NPC1L1), ATP-binding cassette transporter A1 (ABCDA1), scavenger receptor class B type 1 (SR-B1), and cluster of differentiation 36 (CD36).  These proteins are expressed in the retina [65] , suggesting the retina maintains internal lipid processing machinery that involves HDL-like particles of which PK and MK4 are likely components [66]. Genome-wide associations studies have linked these HDL transporters and their receptors to carotenoids levels in the human retina [63], and the transporter ABCDA1 has also been linked to primary open angle glaucoma risk [67]; indicating these transporters and their participation in VK biology need to be considered in further research, if a more complete understanding of the role of VK in the EVS is to be realized.

Thus, a fundamental gap exists with respect to essentially all aspects of the VK forms, tissue distribution, concentrations, and trafficking within the human eye, and to a lesser extent the human brain. These studies are required and urgently needed prior to any well designed clinical trials of therapeutic interventions and solid recommendations with respect to optimized VK dietary intake or supplementation throughout the life cycle.

2.2. Vitamin K dependent proteins in the ocular/visual system.

Having established that VK is found in the mammalian eye, as well as in human, mouse, and rat brains, and that MK4 levels in human decedent brains, are correlated with recognized dementia-related neuropathologies and cognitive function prior to death; it is appropriate to begin to address the nature of VK action in the EVS.

Broadly, VK function can be categorized as canonical, primarily referring to the gamma carboxylation of hepatic coagulation related VKDPs, and secondarily to the gamma carboxylation of non-hepatic VKDPs; and non-canonical, referring largely to VK quinones ability to share electrons in biologic systems.

It has been nearly fifty years since the mode of action of VK, γ-carboxylation of glutamic acid, has been unambiguously demonstrated in relationship to its activation of VKDPs by Nelsestuen et al. in 1974 [68], and noted by Suttie in his excellent review of vitamin K-dependent protein synthesis in 1993[30]. There are currently felt to be 17 VKDPs [33]. Interestingly, γ-carboxyglutamyl carboxylase (GGCX), which is abundantly found in brain tissue [69], as well as in the retina [70], has also been shown to be a VKDP [71], though it is essentially never mentioned in a list of VKDPs.  Importantly, very few works regarding VKDPs in general mention these proteins in the brain, and even fewer, with respect to the EVS.

Ferland in 1998 [32] reviewed the 13 then known VKDPs and classified seven as related to blood coagulation, three related to bone metabolism, and four as “other”, with largely unknown functions, apart from Gas6, as a regulator of cellular growth. No mention of VKDPs in the eye or brain were noted.

Having conducted ground breaking work in brain sphingolipids, as well as the relationship of VK intake and cognitive function in rats and humans, Ferland subsequently published a comprehensive review of the action of VK in the nervous system in 2012 [69], in which the roles of Gas6 in cell survival, growth, and myelinations, and Protein S in signal-mediated neuroprotection, and local antithrombotic activity in the brain, were discussed.  Again, no mention of VK or VKDP action in the EVS was noted.

In an expansive effort, McCann and Ames 2009 [18], systematically reviewed VK and VKDP within the framework of the “Triage Theory” of micronutrient distribution and allocation, which posits that “when the availability of a micronutrient is inadequate, nature insures that micronutrient-dependent functions required for short-term survival are protected at the expense of functions whose lack has only long-term consequences, such as the diseases associated with aging” [18]. This work is the most detailed coverage of the major known VKDPs, and though limited, the only review to mention extrahepatic VKDP and their action in the eye, referencing prothrombin (Factor II) in the cornea, and the role of Tgfbi in corneal dystrophy (which recent research calls into question with respect to its activation by VK [72]).

Before addressing the VKDPs specifically found in the EVS, brief mention should be made of the importance of VK and the seven hepatic VKDP clotting factors with respect to hemorrhagic visual complications. A properly functioning clotting system is essential for preservation of both life and visual function. Vitamin K deficiency in the newborn period can present with blindness in survivors [73]. Children treated with vitamin K antagonists (VKA such as warfarin) and not properly monitored, have been blinded due to orbital hemorrhages [74]. Numerous cases in the literature report major ocular complications associated with the use of VKA in adults as well [75,76]. Thus, disruption of hepatic VK metabolism from any number of causes, has long been known to result in potentially blinding complications, and we can now turn our attention to the lesser known, extrahepatic VKDPs and their localization, and potential importance to the EVS.

To date, four VKDPs along with GGCX have been shown to have expression and activity in ocular tissues. Using technology they largely pioneered and developed to identify and isolate differentially expressed genes from very small human tissue samples [77], Borrás et al in 2000 [78] reported for the first time, that the gene coding for matrix Gla protein (MGP) was among the most highly expressed in human trabecular meshwork tissue. Later in 2000, Canfield et al, after having studied the osteogenic potential of bovine retinal vascular pericytes (BRVP) for more than a decade, reported MGP was differentially expressed by BRVP during deposition of a calcified matrix [79]. Borrás et al. went on to carefully prove over the next two decades that MGP was essential to maintain physiologic intraocular pressure [80], as well as to show the presence of MGP gene expression in the trabecular meshwork (TM), sclera above the TM, in the ciliary muscle, adjacent to the optic nerve in peripapillary sclera [81], and in the vascular smooth muscle cells of the retinal vasculature [82]. Most recently in 2021, Sarosiak et al. [83] demonstrated the presence of MGP, and active VK metabolic pathways, in the corneas of normal controls, and patients with Schnyder corneal dystrophy.

Collett et al. in 2003 reported that bovine retinal capillary pericytes (BRCP) produced Gas6 [84], and Valverde et al. 2004 found Gas6 in bovine vitreous humor [85], while in a series of papers between 2001-2005, Hall et al. demonstrated that both Gas6 and Protein S were essential for the phagocytosis of retinal outer segments (ROS) by the retinal pigment epithelium (RPE) [86–88]. 

Finally, prothrombin (Factor II), has been shown to be produced locally at all levels in human corneas, and participates in corneal wound healing [89]. Table 2 below summarizes the currently known ocular associated VKDP, their location, number of Gla residues, and proposed functions.

Table 2. Summary of ocular related VKDP and their function.

Table 2. Summary of ocular related VKDP and their function.

Author, Year Country [Ref]	Location	Protein [Number of Gla Residues]	Expression	Function
Sarosiak et al. 2021 Poland [83]	Human Cornea	Matrix Gla Protein (MGP) [5 Gla]	Epithelium, Stromal Fibroblasts and Keratinocytes	Essentially unknown, possible maintenance of calcium homeostasis and anti-calcification role. Possible role in calcium signaling of epithelial proliferation and differentiation [53]
Borrás et al. 2000-2021 USA [78,80,81,82]	Human & mouse trabecular meshwork (TM), Peripapillary Sclera (SC), Retinal vascular smooth muscle cells (VSMC)	MGP [5 Gla]	TM, SC, Capillaries, and pericytes	Essential to maintain physiological IOP
Ayala et al. 2007 USA [89]	Human Cornea	Prothrombin [10 Gla]	All layers of the cornea, intracellularly and in extracellular matrix	Production of thrombin, corneal wound healing, regulation of growth factors, and other signaling molecules via protease-activated receptors.
Hall al. 2001-2005 USA [86,87,88]	Rat Photoreceptor Outer Segments (POS), Retinal Pigment Epithelium (RPE)	Growth Arrest Specific 6 (Gas6) [11 Gla], Protein S (PROS1) [11 Gla]	RPE, POS	Phagocytosis of POS by the overlying RPE via vitamin K-dependent gamma-carboxylation of Gas6 and PS in a Ca2+ mediated linking of POS to RPE Mer receptors for phagocytosis
Valverde et al. 2004 USA [85]	Vitreous humor	Gas6 [11 Gla]	Bovine vitreous humor	Gas6/Axl signaling in lens epithelial cells support cell growth and survival.
Collett et al. 2003 UK [84]	Bovine retinal capillary pericytes	Gas6 [11 Gla]	Bovine retinal capillary pericytes	Interactions in regulating osteogenesis and diseases involving ectopic calcification.
Canfield et al. 2000 UK [79]	Bovine retinal capillary pericytes	MGP [5 Gla]	Bovine retinal capillary pericytes	Regulation cell differentiation and calcification

3. Vitamin K and Specific Ocular Conditions

3.1. Glaucoma

Glaucoma is the leading cause of irreversible blindness, with a calculated 3.6 million blind in 2020, and an estimated age adjusted prevalence of 2.04 (per 1000) worldwide[90].  It is a multi-factorial ocular condition characterized by optic neuropathy and generally associated clinically with increased intraocular pressure[91].The ongoing reduction of intraocular pressure remains the only proven treatment for the condition, and currently there is no cure[92,93]. The intraocular pressure is determined by the resistance to aqueous humor flow generated by the trabecular meshwork (TM), located in the anterior chamber of the eye at the juncture of the iris and cornea [94],with most of the resistance believed to be a function of the modulation and turnover of the extracellular matrix (ECM) in the region [95,96].

The VKDP MGP has been conclusively demonstrated to play a central role in glaucoma.  Borrás et al. 2020 [80] have shown that the mouse Mgp gene is both responsible and sufficient to maintain normal pressure in the eye, though the exact mechanisms remain to be determined. This discovery was the result of meticulous work beginning more than two decades ago [77,78], demonstrating that the gene encoding MGP, is among the 10 most expressed genes in the human TM, and that MGP activity correlated with the calcification process [97]. They also demonstrated that MGP is heavily expressed in the TM, regionally in the sclera overlying the trabecular meshwork, and surrounding the optic nerve [81].

A detailed recounting of the twenty-year effort and cardinal milestones in this research achievement from the Borrás lab is beyond the scope of this review, but is a remarkable accomplishment and worthy of recognition-one that may well usher in a new era of glaucoma gene therapy, a welcome option for possible glaucoma treatment in the future.

No studies in humans have yet been done to directly investigate VK with respect to glaucoma. However, Wei et al 2018 [98] demonstrated circulating immature nonphosphorylated and uncarboxylated MGP (dp-ucMGP), a marker of reduced VK nutritional status, is a long-term predictor of reduced retinal arteriolar diameter, and referenced a number of studies linking retinal microvascular traits and generalized arteriolar narrowing with glaucoma [98].  A single in vivo study exploring the effect of dietary PK in a surgically induced ocular hypertension rat model was found [99]. Deng et al. found that rats fed a high PK diet for a total of seven weeks were protected from retinal ganglion cell (RGC) loss and TM injury. MGP levels were supported, and there was a transient reduction in intraocular pressure (IOP) at two weeks. Serum PK levels were 0.4 ± 0.52 ng/mL vs. 7.62 ± 5.98 ng/mL; P = 0.054 in controls vs. the experimental group, which was a 19x elevation, yet no significant adverse effects were found on coagulation parameters or body weight. 

In 2018 a systematic review and meta-analysis of the effects of vitamins on glaucoma, encompassing 629 publications, found only dietary vitamin A to have a significant association with primary open-angle glaucoma (POAG), having a pooled OR [95% CI] of 0.45 [0.30–0.68] (I² = 0%) [100]. The authors noted that no studies specifically related to VK were found, but importantly, four studies related to green leafy vegetables intake, (recently shown in a prospective randomized cross over clinical trial to effect statistically significant improvement in VKDP parameters [68]), demonstrated significant negative associations with POAG. Increased dietary green leafy vegetables intake was associated with a 20-69% lower risk of glaucoma [101–104]. Though the quality of the studies varied, the results suggest that even a relatively modest increase in green leafy vegetables, which are the main source of VK in the diet, may have a significant impact on the risk of glaucoma. Table 3 below provides a summary of the studies.

Table 3. Glaucoma and dietary intake studies.

Table 3. Glaucoma and dietary intake studies.

Author, Year, Country [Ref]	Subjects	Design	Intervention	Findings
Coleman et al. 2008 USA [101]	1,155 women with glaucoma in at least one eye	Observational Cross-sectional cohort	Block Food Frequency Questionnaire	Decreased glaucoma risk by 69% (odds ratio [OR], 0.31; 95% confidence interval [CI], 0.11 to 0.91) in women who consumed ≥ one serving per month of green collards and kale compared with those who consumed < than one serving per month
Moïse et al. 2012 Africa [102]	500 African type II diabetics	Cross-sectional design	Mediterranean-style dietary score (MSDPS) using the Harvard semi quantitative FFQ adapted for Africa.	Regular intake of the Mediterranean Diet and the consumption of locally grown vegetables including Brassica Rapa, dry beans, Abelmoschus esculentus, and Musa acuminata reduced significantly the absolute risk of glaucoma.
Giaconi et al. 2012 USA [103]	584 African-American women participants in the Study of Osteoporotic Fractures	Observational Cross-sectional cohort	The Block Food Frequency Questionnaire	>1 serving/week compared to ≤1 serving/month of collard greens/kale decreased the odds of glaucoma by 57% (OR = 0.43; 95% CI: 0.21–0.85)
Kang et al. 2016 USA [104]	Prospective cohorts of the Nurses’ Health Study (63 893 women; 1984-2012) and the Health Professionals Follow-up Study (41 094 men; 1986-2012)	Prospective cross-sectional observational study	Primary exposure was dietary nitrate intake. Information on diet and potential confounders was updated with validated questionnaires	Very robust study demonstrating greater intake of dietary nitrate and green leafy vegetables was associated with a 20% to 30% lower POAG risk; and a 40%-50% lower risk for POAG with early paracentral VF loss at diagnosis, in 1483 incident cases identified from 63 893 women and 41 094 men followed for more than 25 years

Thus, recent work confirms a role of VK with respect to glaucoma and support the need for further research. A mouse model confirms the essential function of the VKDP MGP in glaucoma which may serve as a powerful platform for future VK ocular research. In vivo studies in the rat have shown that PK may be effective in preserving RGC cells and addressing TM injury. Several observational studies have found that increased VK intake may reduce the risk of glaucoma, and that systemic VK status is associated with retinal arteriolar narrowing, a risk factor associated with glaucoma.

3.2. Cataracts

Cataracts are the leading cause of reversable blindness worldwide [105], with a global age-standardized pooled prevalence estimate (ASPPE) of 17.20% (95% CI 13.39–21.01) [106], indicating that for 1000 people randomly sampled anywhere, 133-210 would be estimated to have cataracts. Age was found to correlate with cataract type directly, and age was the source of variance for cataract prevalence, and regional differences [106]. This is not surprising given the fact that fetal lens cells persist for the lifetime of an individual [107], and are felt to serve as an excellent model of the aging process.  

Despite advancements, unoperated cataracts remain ophthalmology’s major unsolved problem [108], and efforts to train and support additional surgeons cannot keep pace with aging demographics [105]. Measures to prevent or treat cataracts have met with limited success, but antioxidants and free radical scavengers have shown potential in the lab, and thus further research and clinical trials are needed [109].

In a secondary analysis, Camacho-Barcia et al. 2017[15] analyzed prospectively collected PK intake using baseline and yearly food frequency questionnaires in a group of 5860 individuals in the Prevención con Dieta Mediterránea Study (PREDIMED) [110]with a the mean (SD) age of 66.3 (6.1) years, followed for a median of 5.6 years.  After adjusting for multiple potential confounders, individuals in the highest tertile of mean energy-adjusted dietary vitamin K1 intake, had a lower risk of cataract surgery than those in the lowest tertile (HR, 0.71; 95% CI, 0.58-0.88; P = .002). A total of 768 individuals underwent cataract surgery.  Of note, the European Food Safety Authority has set an adequate intake (AI) of 1 μg phylloquinone/kg body weight per day for all age and sex groups [111], and though the PREDIMED study did not report body weights, the average weight for adults in Spain are 82 Kg and 66 Kg for males and females [112], the United States and Canada AI’s are 120 and 90 μg/day[113] . Thus, on average, the estimated daily intake of PK in this cohort was 2.75-5.5 times the recommended AIs on the low and high ends respectively, yet a near doubling of the PK intake from 249.4 to 496.7 µg/d was associated with a 29% reduction in the hazard ratio (HR) for cataract surgeries comparing the lowest to highest tertiles.  A review of the supplemental data reveals that daily average green leafy vegetable intake was 48.2 g/day and 130.2 g/day in the two groups, representing a difference of approximately 1/2 cup of cooked kale per day [113].

Though experts have pointed out a number of limitations in the study methodology with respect to the estimation of dietary PK intake [114]; the study population size, control for multiple confounding dietary and other variables, the firm end point of a large number of surgeries, along with the 29% relative risk reduction in such a clinically relevant indicator that occurred in close to 1 in 8 participants, may well serve as a strong rational for the undertaking of well-designed interventional studies with respect to VK and cataract prevention. Of interest, and possibly strengthening this assertion, is a companion study by the authors [115] reporting on these same individuals, showing that the incidence of cataract surgery was similar in the interventional MedDiet groups supplemented with olive oil or nuts, compared with the low-fat diet group, suggesting that possibly a doubling of PK intake itself may possibly be protective, while other more general dietary factors are not. Certainly, well designed interventional studies will be needed to define possible causality.

In a series of animal studies beginning in 2014, Varsha and Thiagarajan et al. [116–118], demonstrated in a streptozotocin (STZ)-induced diabetic model in Wistar rats, that PK was able to prevent the formation of lens opacity by modulating lens Ca⁺⁺ homeostasis and hyperglycemic effects through direct action on the pancreas. In a second experiment they found that PK was able to reduce rat lens sorbitol via direct competitive inhibition of DL-glyceraldehyde binding to lens aldose reductase 2 (ALR2). Lens calcium in PK treated rats was lower than STZ treated rats and even slightly lower than control.  Likewise, Ca⁺⁺-ATPase activity was higher in PK treated rats compared to the STZ group and controls. This suggested to the authors that PK has potential to inhibit diabetic cataracts by supporting pancreatic function, inhibiting lens oxidative stress, and directly modulating lens Ca⁺⁺ levels. Figure 2, shows PK inhibition of STZ-induced diabetic-cataracts in Group III  from Sai Varsha et al. 2014[118].

Figure 2. Effect of vitamin K1 on diabetic cataractogenesis. Control group I (2a), cortical cataract observed in Group II STZ induced diabetes (2b), treatment of diabetic rat with vitamin K1 prevented appearance of cataract in group III rats (3c). Adapted from: Sai Varsha, M.K.N.; Raman, T.; Manikandan, R. Inhibition of Diabetic-Cataract by Vitamin K1 Involves Modulation of Hyperglycemia-Induced Alterations to Lens Calcium Homeostasis. Experimental Eye Research 2014, 128, 73–82, doi: 10.1016/j.exer.2014.09.007 [118]. Copyright Elsevier-used with permission.

Figure 2. Effect of vitamin K1 on diabetic cataractogenesis. Control group I (2a), cortical cataract observed in Group II STZ induced diabetes (2b), treatment of diabetic rat with vitamin K1 prevented appearance of cataract in group III rats (3c). Adapted from: Sai Varsha, M.K.N.; Raman, T.; Manikandan, R. Inhibition of Diabetic-Cataract by Vitamin K1 Involves Modulation of Hyperglycemia-Induced Alterations to Lens Calcium Homeostasis. Experimental Eye Research 2014, 128, 73–82, doi: 10.1016/j.exer.2014.09.007 [118]. Copyright Elsevier-used with permission.

The human lens is the only transparent, avascular, and nerveless organ in the body [119], and Ca⁺⁺  ion concentrations, which are 10,000-fold reduced across the lens plasma membrane compared to the surrounding aqueous humor, have long been known to be a key factor in lens physiology and pathophysiology, largely serving as secondary messengers to regulate numerous essential cellular processes[120]. Receptor tyrosine kinases (RTK), and G-protein-coupled receptors are the cell plasma membrane receptors that detect extracellular signals and modulate free Ca⁺⁺, thus controlling cell processes such as gene expression, cell proliferation, apoptosis, and cell death [120]. Gap junctions between lens cells serve as channels for the flow of metabolites, small molecules, and ions in the avascular tissue [121]. Mutations in the connexin proteins making up theses junctions disrupts the calcium ion flux, and in the extreme, leads to intracellular calcium precipitation and cataract formation [121]. 

Tyros3, Axl, and Mertk are RTK’s that make up the TAM family of tyrosine kinase receptors that have Gas6 and PS, two VKDPs as their ligands, with important function in the nervous system [122], as well as the retina as demonstrated by Hall et al. [88]. Valverde et al. 2004 [85] have demonstrated Axl expression in rat and bovine lens epithelial cells, as well as in human lens epithelial. They also demonstrated the presence of Gas6 in bovine aqueous humor.  Using a human lens epithelial cell (HLEC) culture model, they show that Gas6 through Axl activation, supports lens epithelial cell growth, survival, and homeostasis. Interestingly, Carnes et al. 2018, report elevated Gas6 mRNA expression in human ciliary bodies, compared to human trabecular meshwork and corneal tissue, suggesting that this important VKDP ligand, may be exported into the aqueous humor, in part to support lens physiology [123]. PS has been found free in aqueous humor in the 7-8 ng/ml range and varies in disease states such as diabetes[124], indicating an additional potential role for VK in homeostatic mechanisms related to diabetic cataracts.

4. Non-canonical Vitamin K functions and ferroptosis

5. Vitamin K, higher cortical visual processing function, and ocular correlates

6. Discussion

7. Clinical considerations

8. Conclusions

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