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Prevalence of vitamin K deficiency in older people with hip fracture

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Celine Bultynck
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N. Munim
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Dominic J Harrington at University of Surrey
Dominic J Harrington
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Introduction: Vitamin K plays an important role in blood coagulation. Diet is the main source of vitamin K and body stores are depleted in days, hence deficiency is common in malnourished older people. A high proportion of people who sustain a hip fracture are already malnourished, compounded by fasting for surgery which might further increase deficiency. We wanted to explore the prevalence of vitamin K deficiency in hip fracture patients and the impact of a short period of fasting. Methods: In consecutive patients hospitalised with a hip fracture, we measured vitamin K and PIVKA-II (undercarboxylated factor II – a marker of subclinical vitamin K status) on admission and on first post-operative day. We excluded those on anticoagulants. Results: N = 62 participated; 4 had missing pre-op vitamin K samples and n = 3 had no surgery leaving n = 55 with paired samples. Mean age was 80.0 ± 9.6 years, 33% males. Prevalence of subclinical vitamin K deficiency on admission was 36% (20/55) based on reference range of > 0.15µg/L. The proportion with subclinical K deficiency after surgery rose to 64% (35/55), p < 0.05. 13% had detectable PIVKA-II concentrations pre-operatively, 15% did post-operatively. None had abnormal prothrombin time. Vitamin K status was not associated with post-operative haemoglobin drop or transfusion requirements. Conclusion: Prevalence of vitamin K deficiency in hip fracture patients is high and increases further following a short period of fasting. Though no significant impact was noted on peri-operative blood loss, larger studies are warranted to explore this, and the potential role of vitamin K supplements peri-operatively.
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Acta Clinica Belgica
International Journal of Clinical and Laboratory Medicine
ISSN: 1784-3286 (Print) 2295-3337 (Online) Journal homepage: https://www.tandfonline.com/loi/yacb20
Prevalence of vitamin K deficiency in older people
with hip fracture
Celine Bultynck, N. Munim, D. J. Harrington, L. Judd, F. Ataklte, Z. Shah & F.
Dockery
To cite this article: Celine Bultynck, N. Munim, D. J. Harrington, L. Judd, F. Ataklte, Z. Shah & F.
Dockery (2019): Prevalence of vitamin K deficiency in older people with hip fracture, Acta Clinica
Belgica, DOI: 10.1080/17843286.2018.1564174
To link to this article: https://doi.org/10.1080/17843286.2018.1564174
Published online: 08 Jan 2019.
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Prevalence of vitamin K deficiency in older people with hip fracture
Celine Bultynck
a
, N. Munim
b
, D. J. Harrington
b
, L. Judd
a
, F. Ataklte
a
, Z. Shah
c
and F. Dockery
a
a
Department of Ageing & Health, Guy’s & St. Thomas’NHS Trust, London, UK;
b
Nutristasis Unit, Guy’s & St. Thomas’NHS Trust, London,
UK;
c
Department of Orthopaedics, Guy’s & St. Thomas’NHS Trust, London, UK
ABSTRACT
Introduction: Vitamin K plays an important role in blood coagulation. Diet is the main source
of vitamin K and body stores are depleted in days, hence deficiency is common in malnour-
ished older people. A high proportion of people who sustain a hip fracture are already
malnourished, compounded by fasting for surgery which might further increase deficiency.
We wanted to explore the prevalence of vitamin K deficiency in hip fracture patients and the
impact of a short period of fasting.
Methods: In consecutive patients hospitalised with a hip fracture, we measured vitamin K and
PIVKA-II (undercarboxylated factor II –a marker of subclinical vitamin K status) on admission
and on first post-operative day. We excluded those on anticoagulants.
Results: N = 62 participated; 4 had missing pre-op vitamin K samples and n = 3 had no
surgery leaving n = 55 with paired samples. Mean age was 80.0 ± 9.6 years, 33% males.
Prevalence of subclinical vitamin K deficiency on admission was 36% (20/55) based on
reference range of > 0.15µg/L. The proportion with subclinical K deficiency after surgery
rose to 64% (35/55), p < 0.05. 13% had detectable PIVKA-II concentrations pre-operatively,
15% did post-operatively. None had abnormal prothrombin time. Vitamin K status was not
associated with post-operative haemoglobin drop or transfusion requirements.
Conclusion: Prevalence of vitamin K deficiency in hip fracture patients is high and increases
further following a short period of fasting. Though no significant impact was noted on peri-
operative blood loss, larger studies are warranted to explore this, and the potential role of
vitamin K supplements peri-operatively.
KEYWORDS
Vitamin K; phylloquinone;
PIVKA-II; coagulation; hip
fracture
Introduction
Vitamin K is the collective name for a group of fat-
soluble compounds whose primary function is to acti-
vate glutamic acid residues (gla). Gla is essential for
the calcium binding capacity (and hence, activation)
of the hepatic procoagulant clotting factors II, VII, IX
and X as well as naturally occurring anticoagulants
protein C, S and Z. Vitamin K therefore, has an impor-
tant role in coagulation and its deficiency is asso-
ciated with excessive bleeding. This is of potential
importance in patients who are undergoing major
surgery such as hip repair or replacement [1–4].
The two natural forms of vitamin K are vitamin K
1
(K
1
),
also known as phylloquinone, and vitamin K
2
(K
2
)series,
also known as the menaquinones. Diet is the main source
of vitamin K. Vitamin K
1
is found in dark green leaved
vegetables and certain vegetable oils. Dietary sources of
K
2
include meat, liver and fermented foods, but their
contribution to total vitamin K intake is small in the
western diet. Vitamin K is predominately stored in the
liver as well as in fatty tissue and reserves are depleted by
fasting periods of as little as three days [2,4,5].
The most widely known laboratory test for vitamin K
deficiency is the prothrombin time (PT). However, this
test is insensitive to mild vitamin K deficiency [6,7].
Serum K
1
can be measured directly and can also be
assessed indirectly by using protein induced by vitamin
K absence-II (PIVKA-II). PIVKA-II concentration reflects
hypocarboxylated prothrombin and thus the functional
effects of vitamin K deficiency. These tests can offer very
sensitive measures of subclinical deficiency, before any
changes are detected in the PT [2,7–10].
A decline in vitamin K
1
concentrations have been
noted in patients following neurosurgery and gastro-
intestinal surgery, though no impact on perioperative
blood transfusion requirements was observed [8,11].
As a high proportion of older hip fracture patients are
already undernourished prior to admission and many
are anaemic, we wanted to ascertain whether vitamin
Kdeficiency is compounded by fasting for surgery in
this group. We also wanted to ascertain whether there
was any impact of deficiency state on subsequent
perioperative blood loss.
Materials and methods
We conducted a prospective cohort study on 62 con-
secutive patients age 60+ years admitted to our
CONTACT Celine Bultynck celinebultynck@gmail.com Department of Ageing & Health, Guy’s & St. Thomas’NHS Trust, Westminster Bridge Rd,
London SE1 7EH, UK
ACTA CLINICA BELGICA
https://doi.org/10.1080/17843286.2018.1564174
© 2019 Acta Clinica Belgica
orthopaedic ward following emergency admission
with a fractured neck of femur. Patients on oral anti-
coagulant drugs, taking vitamin K supplements (or
multivitamins that contain vitamin K), severe liver dis-
ease, deranged coagulation bloods tests at baseline or
known bleeding disorder were excluded. The study
was approved by local Research Ethics Committee
and patients and/or carer (for those lacking capacity)
gave written consent to participate.
Once patients consented to the study, their stored
laboratory samples from admission and first post-
operative day were retrieved for later assay of serum
K
1
and PIVKA-II concentrations by the laboratory. All
blood samples are stored by this hospital’s laboratory
for 5 days as per standard practice. All patients also
had blood panel for haemoglobin, renal function and
coagulation testing as per hip fracture protocol.
Prothrombin analysis was performed using the
Owren PT-INR method and normal reference range
0.9–1.2 was used. Serum measurements of K
1
were
performed by using a modified high-performance
liquid chromatography (HPLC) method with post-col-
umn chemical reduction and fluorescence detection
based on that described by Davidson and Sadowski
[12]. The non-fasting reference range for K
1
in healthy,
normolipaemic adults is 0.15–1.55 µg/L. By participa-
tion in KEQAS, an international scheme that monitors
and reports on the accuracy of vitamin K
1
analysis,
quality assurance was monitored.
Serum PIVKA-II was measured by enzyme-linked
immunosorbent assay (ELISA) based on the method
previously described by Belle et al. [13]. The mono-
clonal antibody (C4B6 MAb) used in this assay is con-
formation-specific such that in the presence of
calcium ions it binds only undercarboxylated species
of prothrombin. Results are reported as arbitrary units
(AU) per millilitre, where 1 AU is equivalent to 1 µg of
multiple PIVKA-II species purified from patients trea-
ted with vitamin K antagonists. Using this assay, the
lower limit of detection for PIVKA-II in adults was <0.2
AU/ml (<200 ng/ml) and detectable PIVKA-II was con-
sidered to reflect subclinical vitamin K deficiency.
Statistical analysis
Statistical analyses were performed using SPSS 25. For
the purpose of analysis, all laboratory values below the
limit of detection for a particular assay were recorded
as the lowest value for that assay. Pearson’s correlation,
chi-squared and student’sttests were used for ana-
lyses, with equivalent non-parametric tests for data not
fitting a normal distribution.
Results
A total of 62 patients agreed to participate. Of those, 4
had missing pre-op vitamin K samples leaving 58 with
baseline levels only. A further 2 had no post-op vita-
min K sample and 1 had conservative management of
their fracture initially with surgery a week later so was
excluded leaving 55 patients with paired samples in
the study. Participants included were aged between
60 and 102. Baseline characteristics are in Table 1.
The prevalence of subclinical vitamin K deficiency on
admission was 36% (20/55) based on normal laboratory
reference range for vitamin K
1
of > 0.15 µg/L as per a
healthy population. The mean vitamin K
1
level was
0.34 ± 1.2 µg/L on admission and 0.15 ± 0.025 µg/L
after surgery. These numbers are comparable to pre-
vious studies in other populations like cancer patients
or morbidly obese patients [2,7]. Those with low vita-
min K levels on admission were frailer as per Clinical
Frailty Scale (CFS) than those with normal vitamin K
levels, but no other significant differences noted. The
proportion of patients with vitamin K deficiency after
the period of fasting for surgery had risen further to
64%, p < 0.001 for comparison to baseline (Figure 1).
Detectable PIVKA-II concentrations were present in
13% of the patients pre-operatively and in 15% post-
operatively. No patients had an abnormal prothrom-
bin time. There was a non-significant tendency to a
greater fall in haemoglobin level post operatively in
those who had low vitamin K status on admission
(p = 0.051, Table 1) but on regression analysis adjust-
ing for other patient characteristics and comorbidities
this was not significant. Similarly the relationship
between the fall in vitamin K levels and post-opera-
tive blood loss was non-significant.
Discussion
In this study, we found a high prevalence of vitamin K
deficiency in patients who had been admitted acutely
with a hip fracture and a further increase in deficiency
state after a short period of fasting for surgery. This is
in keeping with previous studies showing low levels in
Table 1. Patient characteristics expressed as mean±SD, n(%)
or median[interquartile range] as appropriate.
Subclinical vita-
min K deficiency
n=20
Vitamin K
normal
n = 35 p
Age (y) 80 ± 10 79 ± 9 0.673
Charlson comorbidity index ≥3
(%)
6 (30) 11 (31) 0.912
Clinical Frailty Scale ≥5 (%) 16 (80) 12 (34) 0.001
Living alone (%) 14 (70) 20 (57) 0.345
Independently mobile outdoors
(%)
9 (45) 22 (63) 0.199
Baseline Hb (g/L) 121 ± 22 118 ± 18 0.542
Baseline creatinine (µmol/L) 78 [57–102] 72 [56–
100]
0.529
Delay >36hrs for surgery (%) 2 [10]6[17] 0.470
Mean fall in Hb post-operative
(g/L)
−29 ± 14 −21 ± 11 0.051
Patients with a clinically relevant
fall in Hb >20g/L (%)
60 49 0.575
Post-operative blood transfusion
(%)
7 (35) 8 (24) 0.331
2C. BULTYNCK ET AL.
hip fracture patients [14,15], and with studies showing
that serum vitamin K
1
rapidly declines after dietary
restriction though this has not been looked at in hip
fracture patients in the perioperative period before
[2,8]. We did not however observe an adverse impact
of this deficiency state on perioperative bloods loss or
need for blood transfusion though there was a ten-
dency to a greater fall in post-operative haemoglobin
in the K-deficient group. A larger study might have
ascertained this relationship more clearly.
The cohort who had low vitamin K status on admis-
sion were notably frailer despite similar baseline char-
acteristics otherwise, which may reflect their poorer
nutrition, but we did not have weight or body mass
index records to verify this. Frailty was assessed using
the CFS, a practical and efficient tool for measurement
of frailty based on clinical judgement. It is a well
validated and known to be an adverse outcome pre-
dictor in hospitalised older people, but the overall
predictive validity in the surgical setting should be
studied further [16,17].
ietary deficiency of vitamin K is rare in healthy
individuals but is relatively common in those who
are severely ill, who have chronic conditions or
who are malnourished [2,7]. Several studies have
demonstrated that subclinical vitamin K deficiency
is associated with an increased risk of osteoporotic
hip fracture, through synergistic interplay between
vitamin D and vitamin K metabolism. Whether vita-
min K supplementation will reduce the rate of
bone loss or the risk of fracture remains a matter
of debate [1,14,15,18].
Vitamin K
1
is mainly transported in triglyceride-rich
lipoproteins so postprandial triglyceride elevation
might confound measurements [5,7] however most
studies however have not corrected for triglyceride
levels and though our cohort’s blood samples were
non-fasting, it seems likely that the majority will have
eaten little considering the nature of the emergency
admission.
Though PIVKA-II has been found to be a more
sensitive measure of vitamin K status by others [2,8–
10], we did not see a significant rise in PIVKA-II post-
operatively. A possible explanation for this is the
known inter-subject variability in the amount of
PIVKA-II released into the circulation, as well as the
short fasting period and the half-life of its clearance.
Prothrombin has the longest half-life of the vitamin K-
dependent proteins (60 h), so there is a lag phase
while fully carboxylated prothrombin is catabolised
and gradually replaced with undercarboxylated pro-
thrombin species. The second sample was collected
during the first post-operative day, so this suggests
the lack of postoperative PIVKA-II detection is likely
related to early measurement [11,19]. In future
research we would propose to assay PIVKA-II on the
third and fifth post-operative days.
Another caveat to our results is that the contribu-
tion of vitamin K
2
to the overall vitamin K status was
not considered. However, previous studies have
shown that the role of K
2
in the production of coa-
gulation factors in the western population is
small [2,20].
In conclusion, the prevalence of vitamin K defi-
ciency in hip fracture patients is high and higher still
following a short period of fasting, by which time the
majority of our cohorts were deficient. Though no
significant impact was noted on clinical meaningful
consequences like perioperative bleeding or need of
transfusion, a larger study would be needed to
explore this further and to address to role if any, for
vitamin K supplementation keeping in mind the fra-
gile balance between bleeding and thrombotic risk in
the perioperative period.
Figure 1. Peri-operative change in vitamin K
1
concentration.
ACTA CLINICA BELGICA 3
Summary table
What is known about this topic:
●Vitamin K has an important role in normal coa-
gulation pathways.
●As diet is the main source of vitamin K, deficiency
is common in malnourished patients, including
those with hip fracture.
What this paper adds:
●The high prevalence of subclinical vitamin K defi-
ciency in hip fracture patients is exacerbated
further by a short period of fasting before surgery.
●Vitamin K deficiency is associated with increased
frailty in hip fracture patients.
●Vitamin K
1
deficiency was not associated with
peri-operative blood loss in this group, but larger
studies would be needed to ascertain this
Summary sentence
This work represents an advance in biomedical
science because it shows that vitamin K deficiency
worsens after a short period of fasting in hip fracture
patients, which has not been demonstrated in this
patient population to date.
Disclosure statement
No potential conflict of interest was reported by the authors.
ORCID
Celine Bultynck http://orcid.org/0000-0002-9258-9005
D. J. Harrington http://orcid.org/0000-0003-4786-9240
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ACTA CLINICA BELGICA 5
... 20 These actions that can inhibit bone loss, along with vitamin K administration found to increase osteoblast like actions, as well as bone mineral density in cases of osteoporosis, 20 can potentially have a marked effect on preserving bone mass in cases vulnerable to vitamin K deficiencies. 6 An additional related role for vitamin K points to a favorable influence not only on osteoporosis risk, but on hip fracture risk and injuries, as well surgical outcomes post hip fracture, 21 other pathological fractures and vascular calcifications 22 due to its effect on bone turnover physiology and profiles. 23 Another report has revealed that a low intake of vitamin K is associated with an increase in bone deterioration, 8 as well as the risk of hip fracture in the general population. ...
... Bultynck et al. 21 The prevalence of a subclinical vitamin K deficiency on admission was 36% (20/55) based on reference range of > 0.15µg/L ...
Vitamin K and hip fractures what do we know
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Hip fractures among the older adult population remain highly prevalent oftentimes life-threatening events despite decades of efforts to study their causes and implement preventive endeavors. Even more concerning is the possible unabated prevalence of subsequent even more debilitating second or third hip fractures among primary hip fracture survivors. In an effort to explore if indeed there is current evidence of a key overlooked role for vitamin D as far as its probable benefits for preventing or mitigating hip fracture debility and speeding up the optimal recovery post hip fractures goes, this report examines most of the currently available peer reviewed articles listed on the PUBMED data base as of July 1 2021-July 10 2022 and some background material on this topic. It is concluded that while careful usage of vitamin D in cases of risk or deficiency may afford both preventive and optimal recovery opportunities towards reducing the persistent global age-associated hip fracture burden, as well as the burden of acquiring a second or third hip fracture, no current conclusive evidence prevails in this regard.
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... visser et al. hospitalized with a hip fracture had their plasma vitamin K status assessed 1 day following emergency surgery (Bultynck, Munim, and Harrington 2020). The proportion with subclinical K deficiency after surgery was 64% on the first postoperative day. ...
... vitamin K deficiency = >0.15 µg/l, the lower limit of detection for PivKa-ii in adults was (>2 μg/l) and detectable PivKa-ii was considered to reflect subclinical vitamin K deficiency (Bultynck, Munim, and Harrington 2020). PivKa-ii = protein induced by vitamin K absence-ii; Hem = hemiarthroplasty; tHr = total hip replacement; Postop = postoperative; rCt = randomized controlled trial; Pros = prospective. ...
The effects of cardiovascular and orthopaedic surgery on vitamin concentrations: a narrative review of the literature and mechanisms of action
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Given the rise in worldwide chronic diseases, supplemented by an aging population, the volume of global major surgeries, encompassing cardiac and orthopedic procedures is anticipated to surge significantly. Surgical trauma can be accompanied by numerous postoperative complications and metabolic changes. The present review summarized the results from studies assessing the effects of orthopedic and cardiovascular surgery on vitamin concentrations, in addition to exploring the possible mechanisms associated with changes in concentrations. Studies have revealed a potentially severe depletion in plasma/serum concentrations of numerous vitamins following these surgeries acutely. Vitamins C, D and B1 appear particularly vulnerable to significant depletions, with vitamin C and D depletions consistently transpiring into inadequate and deficient concentrations, respectively. The possible multifactorial mechanisms impacting postoperative vitamin concentrations include changes in hemodilution and vitamin utilization, redistribution, circulatory transport and absorption. For a majority of vitamins, there has been a lack of investigation into the effects of both, cardiac and orthopedic surgery. Additionally, studies were predominantly restricted to short-term postoperative investigations, primarily performed within the first postoperative week of surgery. Overall, results indicated that further examination is necessary to determine the severity and clinical significance of the possible depletions in vitamin concentrations that ensue cardiovascular and orthopedic surgery.
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... Vitamin K deficiency in pregnant women can lead to difficulty in stopping bleeding and impaired blood coagulation and may cause bleeding in newborns. Research also indicates that low dietary intake of vitamin K is associated with decreased bone density in women [34,35] and may increase the risk of hip fractures [36]. Considering the hazards of vitamin E and K deficiency, pregnant women in the advanced age group may need to supplement vitamin E and K appropriately during mid-pregnancy, more than those in the age-matched group. ...
Analysis of Differences in the Serum Levels of Various Vitamins During Pregnancy: Effects of Gestational Stage and Age
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Background Pregnant women exhibit an increased demand for nutrients, including vitamins, and a deficiency in vitamins can increase the risk of various pregnancy-related diseases. This study aims to evaluate the vitamin levels in women of different age groups and gestational stages in order to provide targeted dietary guidance and vitamin supplementation strategies. Methods Pregnant women who registered and attended regular prenatal check-ups at Hangzhou Women’s Hospital from January to December 2021 were selected as study participants. Ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was used to quantitatively determine the concentrations of vitamins A, D, E, K, B1, B2, B9 (folic acid), and B12 in the serum. Results The serum vitamin A, B1, and B9 levels decreased with gestational age in the age-matched group, while the vitamin E level increased slightly (p < 0.05). In the advanced-aged group, the levels of vitamins A, B1, B2, and B9 decreased with gestational age, but the levels of vitamins D3, E, K, and B12 slightly increased (p < 0.05). In mid-pregnancy, age-matched women had slightly greater serum levels of vitamins E and K than did women in the advanced-aged group (Z = –2.67, p = 0.008; Z = –2.46, p = 0.014). In late pregnancy, significant differences existed in the serum levels of vitamins B2 and B12 between the two age groups (Z = –2.67, p = 0.008; Z = –2.50, p = 0.013). Conclusions Vitamin levels varied by gestational stage and age during pregnancy, suggesting that vitamin supplementation should be individualized and stage-adjusted to improve maternal and child health.
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... 61,62 Increased VK intake is effective in reducing ucOC levels, favoring bone renewal and enhancing bone density, 63 and maintaining VK intake reduces the prevalence of hip fractures. 64 In a study linking VK1 to bone health in postmenopausal women, VK1 can reduced the risk of fracture in postmenopausal osteoporosis and enhanced hip joint strength. 65 Long-term stable intake of VK1 can reduce bone loss and help reduce the incidence of fractures, indicating that VK may be beneficial for inhibiting bone resorption and maintaining bone formation. ...
Vitamin K: Infection, Inflammation, and Auto-Immunity
Article
Full-text available
  • Feb 2024
Vitamin K (VK) comprises a group of substances with chlorophyll quinone bioactivity and exists in nature in the form of VK1 and VK2. As its initial recognition originated from the ability to promote blood coagulation, it is known as the coagulation vitamin. However, based on extensive research, VK has shown potential for the prevention and treatment of various diseases. Studies demonstrating the beneficial effects of VK on immunity, antioxidant capacity, intestinal microbiota regulation, epithelial development, and bone protection have drawn growing interest in recent years. This review article focuses on the mechanism of action of VK and its potential preventive and therapeutic effects on infections (eg, asthma, COVID-19), inflammation (eg, in type 2 diabetes mellitus, Alzheimer’s disease, Parkinson’s disease, cancer, aging, atherosclerosis) and autoimmune disorders (eg, inflammatory bowel disease, type 1 diabetes mellitus, multiple sclerosis, rheumatoid arthritis). In addition, VK-dependent proteins (VKDPs) are another crucial mechanism by which VK exerts anti-inflammatory and immunomodulatory effects. This review explores the potential role of VK in preventing aging, combating neurological abnormalities, and treating diseases such as cancer and diabetes. Although current research appoints VK as a therapeutic tool for practical clinical applications in infections, inflammation, and autoimmune diseases, future research is necessary to elucidate the mechanism of action in more detail and overcome current limitations.
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... This conclusion is supported by a study revealing that reduced levels of both vitamin D and K, is associated with adverse cardiac remodeling, and generally all-cause of mortality in men and women [212]. In terms of skeletal health, vitamin K deficiency was found to be prevalent among hip fracture patients [213]. ...
Fat‑soluble vitamins: updated review of their role and orchestration in human nutrition throughout life cycle with sex differences
Article
Full-text available
  • Sep 2022
  • NUTR METAB
Age and Gender are vital determinants for the micronutrient demands of normal indviduals. Among these micronutrients are vitamins that are required in small amounts for optimum metabolism, homeostasis, and a healthy lifestyle, acting as coenzymes in several biochemical reactions. The majority of previous studies have examined such issues that relates to a specific vitamin or life stage, with the majority merely reporting the effect of either excess or deficiency. Vitamins are classified into water-soluble and fat-soluble components. The fat-soluble vitamins include vitamins (A, D, E, and K). Fat-soluble vitamins were found to have an indisputable role in an array of physiological processes such as immune regulation, vision, bone and mental health. Nonetheless, the fat-soluble vitamins are now considered a prophylactic measurement for a multitude of diseases such as autism, rickets disease, gestational diabetes, and asthma. Herein, in this review, a deep insight into the orchestration of the four different fat-soluble vitamins requirements is presented for the first time across the human life cycle beginning from fertility, pregnancy, adulthood, and senility with an extensive assessment ofthe interactions among them and their underlying mechanistic actions. The influence of sex for each vitamin is also presented at each life stage to highlight the different daily requirements and effects.
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... A systematic review of vitamin K usage to prevent fractures in older women has further shown that the presence of vitamin K1 ia indeed quite promising [43], despite contrary findings in a case series of Chinese adults [44]. Moreover, a role for depressed circulating vitamin K levels during the fracture healing period has been shown to influence bone recovery processes [45], especially if persistently low vitamin K intakes are identified [38,41], as those exhibiting high levels of vitamin K deficiency [46] also tend to show excess bone fragility levels. ...
Vitamin K, Osteoporosis, and Hip Fragility Fractures: A Review of Vitamin K Bone Impacts
Article
Full-text available
  • May 2022
This mini review examines whether: 1) Vitamin K, an important dietary compound that can also be partially synthesized intrinsically is a potentially important bone building or modeling determinant whose presence might influence the onset and progression of osteoporosis a key determinant of fragility fractures and 2) whether any evidence points to its application as being desirable among vulnerable aging adults with low vitamin K status or at risk for fragility fractures for other reasons.
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... [6] Vitamin K is stored within the body for short periods and is easily eliminated. [7] Therefore, vitamin K should be supplied regularly through oral intake or produced by the gastrointestinal microbiome in the large intestine. [8] Although vitamin K deficiency is rare among the population with normal oral intake, it can be induced due to poor oral intake (such as in hyperemesis gravidarum), gastrointestinal diseases that prevent vitamin K absorption, or liver diseases. ...
Fetal intracranial hemorrhage and maternal vitamin K deficiency induced by total parenteral nutrition: A case report
Article
Full-text available
  • Jan 2022
Rationale: Fetal brain hemorrhage is rare. It is caused mainly by maternal trauma or fetal coagulation disorder, but in some cases, vitamin K deficiency may be the cause. Patient concerns: We describe the case of a pregnant woman with bowel obstruction who was susceptible to vitamin K deficiency due to oral diet restriction, decreased intestinal absorption, and limited intravenous vitamin K supplementation. Diagnosis: After 18 days of intermittent total parenteral nutrition, acute onset of severe fetal brain hemorrhage developed. Interventions: After acute onset of fetal brain hemorrhage, the patient underwent an emergency cesarean section at 25 + 3 weeks of gestation due to fetal non-reassuring fetal monitoring. Outcomes: The Apgar score at birth was 0/0, and despite cardiopulmonary resuscitation, neonatal death was confirmed. After the baby was delivered, we checked the maternal upper abdominal cavity and found a massive adhesion in the small bowel to the abdominal wall near the liver and stomach with an adhesion band. The adhesion band, presumably a complication of previous hepatobiliary surgery, appeared to have caused small bowel obstruction. Adhesiolysis between the small bowel and abdominal wall was performed. Lessons: This case demonstrates that even relatively short-term total parenteral nutrition can cause severe fetal brain hemorrhage. Vitamin K supplementation is required for mothers who are expected to be vitamin K deficient, especially if they are on total parenteral nutrition for more than 3 weeks.
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... Feskanich et al. showed that women aged 38-74 years with higher daily VK intake had lower serum concentrations of ucOC and a 30% reduction in the risk of hip fracture compared to women with an intake of less than 109 μg VK per day [66]. Equally, the prevalence of VK deficiency was found to be higher in older patients (mean age 80.0) with hip fractures than those without [60]. ...
The Role of Vitamin K in Humans: Implication in Aging and Age-Associated Diseases
Article
Full-text available
  • Apr 2021
As human life expectancy is rising, the incidence of age-associated diseases will also increase. Scientific evidence has revealed that healthy diets, including good fats, vitamins, minerals, or polyphenolics, could have antioxidant and anti-inflammatory activities, with antiaging effects. Recent studies demonstrated that vitamin K is a vital cofactor in activating several proteins, which act against age-related syndromes. Thus, vitamin K can carboxylate osteocalcin (a protein capable of transporting and fixing calcium in bone), activate matrix Gla protein (an inhibitor of vascular calcification and cardiovascular events) and carboxylate Gas6 protein (involved in brain physiology and a cognitive decline and neurodegenerative disease inhibitor). By improving insulin sensitivity, vitamin K lowers diabetes risk. It also exerts antiproliferative, proapoptotic, autophagic effects and has been associated with a reduced risk of cancer. Recent research shows that protein S, another vitamin K-dependent protein, can prevent the cytokine storm observed in COVID-19 cases. The reduced activation of protein S due to the pneumonia-induced vitamin K depletion was correlated with higher thrombogenicity and possibly fatal outcomes in COVID-19 patients. Our review aimed to present the latest scientific evidence about vitamin K and its role in preventing age-associated diseases and/or improving the effectiveness of medical treatments in mature adults ˃50 years old.
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Trainingstherapie und Basistherapie bei OsteoporoseExercise therapy and basic treatment for osteoporosis
Article
  • Sep 2023
Physical training is an important component in the prophylaxis of osteoporosis and the prevention of fractures. Physical training not only has a direct effect on muscle strength and muscular performance, but also on the risk of falling and the fear of falling. Therefore, physical training is also an integral part of the basic treatment for osteoporosis. The recommendations for basic treatment are an adequate intake of nutrients, including protein in particular. The intake of calcium and vitamin D in sufficient quantities is also important and, in the case of specific drug therapy, also to avoid side effects and to ensure the therapeutic effect. This article summarizes the recommendations of the updated S3 guideline on the diagnosis and treatment of osteoporosis and explains the background for the recommendations included.
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Detection of subclinical vitamin K deficiency in neurosurgery with PIVKA-II
Article
Full-text available
  • Mar 2017
Vitamin K is known for supporting the carboxylation of hepatic coagulation proteins. Levels of proteins induced by vitamin K absence for factor II (PIVKA-II) reflect hypocarboxylated prothrombin and can be used to detect subclinical vitamin K deficiency. The aim of this study was to determine the prevalence of perioperative subclinical vitamin K deficiency among neurosurgical patients using PIVKA-II and investigate the existence of any correlation to standard coagulation assays. Also, the antitumor effects of vitamin K were reviewed. Thirty-five patients undergoing brain tumor resection were included. Blood samples were drawn preoperatively, at the end of surgery and in the morning after surgery. In addition to PIVKA-II, factor II and the Owren and Quick prothrombin times were analyzed. Seventeen of 35 patients had elevated PIVKA-II levels before surgery, which continued to be above normal range postoperatively. Median PIVKA-II and Owren prothrombin time (PT-INR) were increased on the morning day 1 postoperatively compared to before surgery, whereas Quick end-stage prothrombin time (EPT) decreased and factor II was unaffected. Postoperative complications were connected to high PIVKA-II increases. Positive correlations between PIVKA-II and factor II and body mass index (BMI) were found. In conclusion, PIVKA-II was increased in many patients preoperatively and then increased by the morning following surgery. Standard coagulation assays were largely non-pathological. Correlations were demonstrated between PIVKA-II and factor II and BMI. The effect of perioperative treatment with different vitamin K supplements should be investigated in future studies, as well as clinical trials evaluating their antitumor effects.
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The Gap Between Clinical Research and Standard of Care: A Review of Frailty Assessment Scales in Perioperative Surgical Settings
Article
Full-text available
  • Jul 2016
The elderly population in the United States is increasing exponentially in tandem with risk for frailty. Frailty is described by a clinically significant state where a patient is at risk for developing complications requiring increased assistance in daily activities. Frailty syndrome studied in geriatric patients is responsible for an increased risk for falls, and increased mortality. In efforts to prepare for and to intervene in perioperative complications and general frailty, a universal scale to measure frailty is necessary. Many methods for determining frailty have been developed, yet there remains a need to define clinical frailty and, therefore, the most effective way to measure it. This article reviews six popular scales for measuring frailty and evaluates their clinical effectiveness demonstrated in previous studies. By identifying the most time-efficient, criteria comprehensive, and clinically effective scale, a universal scale can be implemented into standard of care and reduce complications from frailty in both non-surgical and surgical settings, especially applied to the perioperative surgical home model. We suggest further evaluation of the Edmonton Frailty Scale for inclusion in patient care.
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Frailty measurement in research and clinical practice: A review
Article
Full-text available
  • Mar 2016
One of the leading causes of morbidity and premature mortality in older people is frailty. Frailty occurs when multiple physiological systems decline, to the extent that an individual's cellular repair mechanisms cannot maintain system homeostasis. This review gives an overview of the definitions and measurement of frailty in research and clinical practice, including: Fried's frailty phenotype; Rockwood and Mitnitski's Frailty Index (FI); the Study of Osteoporotic Fractures (SOF) Index; Edmonton Frailty Scale (EFS); the Fatigue, Resistance, Ambulation, Illness and Loss of weight (FRAIL) Index; Clinical Frailty Scale (CFS); the Multidimensional Prognostic Index (MPI); Tilburg Frailty Indicator (TFI); PRISMA-7; Groningen Frailty Indicator (GFI), Sherbrooke Postal Questionnaire (SPQ); the Gérontopôle Frailty Screening Tool (GFST) and the Kihon Checklist (KCL), among others. We summarise the main strengths and limitations of existing frailty measurements, and examine how well these measurements operationalise frailty according to Clegg's guidelines for frailty classification — that is: their accuracy in identifying frailty; their basis on biological causative theory; and their ability to reliably predict patient outcomes and response to potential therapies.
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Concepts and Controversies in Evaluating Vitamin K Status in Population-Based Studies
Article
Full-text available
  • Jan 2016
A better understanding of vitamin K’s role in health and disease requires the assessment of vitamin K nutritional status in population and clinical studies. This is primarily accomplished using dietary questionnaires and/or biomarkers. Because food composition databases in the US are most complete for phylloquinone (vitamin K1, the primary form in Western diets), emphasis has been on phylloquinone intakes and associations with chronic diseases. There is growing interest in menaquinone (vitamin K2) intakes for which the food composition databases need to be expanded. Phylloquinone is commonly measured in circulation, has robust quality control schemes and changes in response to phylloquinone intake. Conversely, menaquinones are generally not detected in circulation unless large quantities are consumed. The undercarboxylated fractions of three vitamin K-dependent proteins are measurable in circulation, change in response to vitamin K supplementation and are modestly correlated. Since different vitamin K dependent proteins are implicated in different diseases the appropriate vitamin K-dependent protein biomarker depends on the outcome under study. In contrast to other nutrients, there is no single biomarker that is considered a gold-standard measure of vitamin K status. Most studies have limited volume of specimens. Strategic decisions, guided by the research question, need to be made when deciding on choice of biomarkers.
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A combination of low serum concentrations of vitamins K1 and D is associated with increased risk of hip fractures in elderly Norwegians: a NOREPOS study
Article
Full-text available
  • Dec 2015
The present study investigated the risk of incident hip fractures according to serum concentrations of vitamin K1 and 25-hydroxyvitamin D in elderly Norwegians during long-term follow-up. The results showed that the combination of low concentrations of both vitamin D and K1 provides a significant risk factor for hip fractures. Introduction This case-cohort study aims to investigate the associations between serum vitamin K1 and hip fracture and the possible effect of 25-hydroxyvitamin D (25(OH)D) on this association. Methods The source cohort was 21,774 men and women aged 65 to 79 years who attended Norwegian community-based health studies during 1994–2001. Hip fractures were identified through hospital registers during median follow-up of 8.2 years. Vitamins were determined in serum obtained at baseline in all hip fracture cases (n = 1090) and in a randomly selected subcohort (n = 1318). Cox proportional hazards regression with quartiles of serum vitamin K1 as explanatory variable was performed. Analyses were further performed with the following four groups as explanatory variable: I: vitamin K1 ≥ 0.76 and 25(OH)D ≥ 50 nmol/l, II: vitamin K1 ≥ 0.76 and 25(OH)D < 50 nmol/l, III: vitamin K1 < 0.76 and 25(OH)D ≥ 50 nmol/l, and IV: vitamin K1 < 0.76 and 25(OH)D < 50 nmol/l. Results Age- and sex-adjusted analyses revealed an inverse association between quartiles of vitamin K1 and the risk of hip fracture. Further, a 50 % higher risk of hip fracture was observed in subjects with both low vitamin K1 and 25(OH)D compared with subjects with high vitamin K1 and 25(OH)D (HR 1.50, 95 % CI 1.18–1.90). The association remained statistically significant after adjusting for body mass index, smoking, triglycerides, and serum α-tocopherol. No increased risk was observed in the groups low in one vitamin only. Conclusion Combination of low concentrations of vitamin K1 and 25(OH)D is associated with increased risk of hip fractures.
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Perioperative changes in PIVKA-II
Article
Full-text available
  • Jul 2015
Proteins induced by vitamin K absence for factor II (PIVKA-II) is an enzyme-linked immunosorbent assay that monitors uncarboxylated prothrombin and responds to vitamin K deficits prior to changes in the prothrombin test. The aim of this project was to study perioperative PIVKA-II changes during various types of surgery in a prospective observational study. Patients undergoing abdominal or orthopaedic surgery were included. Blood was sampled on the day of surgery (preoperatively) and up to 5 days after surgery. The activated partial thromboplastin time, Quick and Owren prothrombin times were analyzed, together with PIVKA-II. Thirty-nine patients were included, 27 +male and 12 +female. All but 7 +patients had elevated PIVKA-II levels preoperatively. PIVKA-II levels had already increased significantly (p < 0.017) on day 1 after surgery as compared to presurgery plasma levels. The median PIVKA-II was highest on day 5. Routine tests were mostly normal. No significant difference in PIVKA-II was seen when comparing patients undergoing abdominal versus orthopaedic surgeries. There was no significant correlation between PIVKA-II and routine coagulation tests. Patients with anterior resection, emergency laparotomy and emergency hip fractures had higher postoperative increases, which could be linked to increased gastrointestinal recovery times, paralytic ileus, peritonitis and comorbidities. PIVKA-II levels increase during the perioperative period, despite mostly normal routine coagulation tests. Pre- and perioperative vitamin K supplementation in patients with elevated PIVKA-II levels should be studied, and its clinical significance be defined in future studies.
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Assessment of Potential Biomarkers of Subclinical Vitamin K Deficiency in Patients with End-Stage Kidney Disease
Article
Full-text available
  • Jun 2014
A significant proportion of hemodialysis patients have functional, but modifiable, vitamin K deficiency. To determine the correlates of poor vitamin K status in hemodialysis patients. Cross-sectional study. Hemodialysis units at Kingston General Hospital and its satellite centres, Ontario, Canada. Patients undergoing outpatient hemodialysis for end-stage kidney disease. Serum concentrations of phylloquinone, undercarboxylated prothrombin, also known as protein induced by vitamin K absence or antagonism - factor II (PIVKA-II), and the percentage of undercarboxylated osteocalcin (%ucOC). Vitamin K status was determined in fasting blood samples of hemodialysis patients. Bivariate relationships were examined using parametric and non-parametric statistics as appropriate. Multivariable linear regression models were applied to identify predictors of vitamin K status. Among 44 HD patients, criteria for subclinical vitamin K deficiency were met in 13.6% (phylloquinone < 0.4 nmol/L), 51% (%ucOC > 20%) and 90.9% (PIVKA-II > 2.0 nmol/L) of subjects. Phylloquinone levels were positively associated with total cholesterol, triglyceride levels and non-smoking status. Higher %ucOC was associated with increased calcium-phosphate product. Increased PIVKA-II levels were observed with advancing age, reduced dialysis adequacy, lower HDL and a history of coronary artery disease. There were no associations found among the individual biomarkers of vitamin K status. In a multi-variable model, triglycerides were the only significant predictor of phylloquinone levels, while increasing phosphate and decreasing PTH were independent predictors of %ucOC. PIVKA-II levels increased by 0.54 nmol/L for every 10-year increase in age. Observational study; small sample size. A significant proportion of HD patients met criteria for subclinical vitamin K deficiency. Of the biomarkers measured, PIVKA-II may be superior given its independence of renal function or dyslipidemia, both of which may confound the other vitamin K biomarkers. Studies in patients with ESKD linking biomarkers of vitamin K status to important patient outcomes, including cardiovascular disease, nutritional status and mortality, are required in order to determine the optimal biomarker for evaluating vitamin K status in this particular population.
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Key Pathways and Regulators of Vitamin K Function and Intermediary Metabolism
Article
  • Aug 2018
Vitamin K (VK) is an essential cofactor for the post-translational conversion of peptide-bound glutamate to γ-carboxyglutamate. The resultant vitamin K-dependent proteins are known or postulated to possess a variety of biological functions, chiefly in the maintenance of hemostasis. The vitamin K cycle is a cellular pathway that drives γ-carboxylation and recycling of VK via γ-carboxyglutamyl carboxylase (GGCX) and vitamin K epoxide reductase (VKOR), respectively. In this review, we show how novel molecular biological approaches are providing new insights into the pathophysiological mechanisms caused by rare mutations of both GGCX and VKOR. We also discuss how other protein regulators influence the intermediary metabolism of VK, first through intestinal absorption and second through a pathway that converts some dietary phylloquinone to menadione, which is prenylated to menaquinone-4 (MK-4) in target tissues by UBIAD1. The contribution of MK-4 synthesis to VK functions is yet to be revealed. Expected final online publication date for the Annual Review of Nutrition Volume 38 is August 21, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Vitamin K plasma levels determination in human health
Article
  • Jan 2016
Vitamin K (phylloquinone or vitamin K1 and menaquinones or vitamin K2) plays an important role as a cofactor in the synthesis of hepatic blood coagulation proteins, but recently has also aroused an increasing interest for its action in extra-hepatic tissues, in particular in the regulation of bone and vascular metabolism. The accurate measurement of vitamin K status in humans is still a critical issue. Along with indirect assays, such as the undercarboxylated fractions of vitamin K-dependent proteins [prothrombin, osteocalcin (OC), and matrix gla protein], the direct analysis of blood levels of phylloquinone and menaquinones forms might be considered a more informative and direct method for assessing vitamin K status. Different methods for direct quantification of vitamin K serum levels are available. High-performance liquid chromatography (HPLC) methods coupled with post-column reduction procedures and fluorimetric or electrochemical detection are commonly used for food and blood analysis of phylloquinone, but they show some limitations when applied to the analysis of serum menaquinones because of interferences from triglycerides. Recent advancements include liquid chromatography tandem mass spectrometry (LCMS/MS) detection, which assures higher specificity. The optimization and standardization of these methods requires specialized laboratories. The variability of results observed in the available studies suggests the need for further investigations to obtain more accurate analytical results.
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Vitamin K and other markers of micronutrient status in morbidly obese patients before bariatric surgery
Article
Background Micronutrient deficiencies occur in morbidly obese patients. The aim of this study was to assess vitamin deficiencies prior to bariatric surgery including vitamin K about which there is little data in this population.MethodsA prospective assessment of 118 consecutive patients was performed. Clinical allied with haematological and biochemical variables were measured. Micronutrients measured included vitamins K1, PIVKA-II (protein-induced in vitamin K absence factor II), vitamin D, vitamin B12 (holotranscobalamin), iron, transferrin and folate.ResultsPatients were aged 49 ± 11 [mean (SD, standard deviation)] years, body mass index (BMI) 50 ± 8 kg/m2, 66% female and 78% Caucasian. Hypertension was present in 47% and type 2 diabetes in 32%. Vitamin D supplements had been prescribed in 8%. Micronutrient insufficiencies were found for vitamin K (40%), vitamin D (92%) and vitamin B12 (25%), and also iron (44%) and folate (18%). Normocalcaemic vitamin D insufficiency with secondary hyperparathyroidism was present in 18%. Iron and transferrin levels were associated with age, sex and estimated glomerular filtration rate. Vitamin K levels were associated with age, and inversely with BMI and diabetes mellitus; and PIVKA-II with smoking, triglycerides and liver function markers. Vitamin D levels were associated with statin use and prescription of supplements and inversely with BMI. Vitamin B12 levels were associated with ethnicity and HbA1c.Conclusion Micronutrient status shows differing relationships with age, gender and BMI. Vitamin K insufficiency was present in 40% and not related to deficiencies in other vitamins or micronutrients. Vitamin D and vitamin K supplementation should be considered prebariatric surgery in patients with diabetes or severe insulin resistance.
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