Vitamin K Deficiency Research Articles

Vitamin K2 in Health and Disease: A Clinical Perspective.

Vitamins are essential organic compounds that vary widely in chemical structure and are vital in small quantities for numerous biochemical and biological functions. They are critical for metabolism, growth, development and maintaining overall health. Vitamins are categorised into two groups: hydrophilic and lipophilic. Vitamin K (VK), a lipophilic vitamin, occurs naturally in two primary forms: phylloquinone (VK1), found in green leafy vegetables and algae, and Menaquinones (VK2), present in certain fermented and animal foods and widely formulated in VK supplements. This review explores the possible factors contributing to VK deficiency, including dietary influences, and discusses the pharmacological and therapeutic potential of supplementary VK2, examining recent global clinical studies on its role in treating diseases such as osteoporosis, osteoarthritis, rheumatoid arthritis, cardiovascular disease, chronic kidney disease, diabetes, neurodegenerative disorders and cancers. The analysis includes a review of published articles from multiple databases, including Scopus, PubMed, Google Scholar, ISI Web of Science and CNKI, focusing on human studies. The findings indicate that VK2 is a versatile vitamin essential for human health and that a broadly positive correlation exists between VK2 supplementation and improved health outcomes. However, clinical data are somewhat inconsistent, highlighting the need for further detailed research into VK2's metabolic processes, biomarker validation, dose-response relationships, bioavailability and safety. Establishing a Recommended Daily Intake for VK2 could significantly enhance global health.

Vitamin K Prescribing Trends Among Critically Ill Children Hospitalized for Sepsis: A Multicenter Observational Cohort Study.

Objective: Vitamin K (VK) is commonly prescribed for pediatric sepsis-induced coagulopathy without trial-derived evidence to support its use for this indication. The purpose of this study was to characterize national prescribing trends for VK in this population. Patients and Methods: This is a multicenter retrospective cohort study using the Pediatric Health Information System registry including children 0 to 17 years of age hospitalized for sepsis in the pediatric intensive care unit from January 2016 through December 2022. The primary outcome was overall, annual, and center-specific VK prescribing rates. Descriptive data included demographics, length of stay, and rates of VK deficiency, hepatic insufficiency, red blood cell (RBC) transfusion, venous thromboembolism (VTE), and mortality. VK prescribing trends were assessed using Joinpoint regression. Descriptive statistics employed included Wilcoxon rank-sum, student's t, and chi-square tests. Results: Of the 31 221 encounters studied, 4539 (14.6%) were prescribed VK (median center-specific rate: 14.2%; interquartile range [IQR]: 8.8-21%) with a linear annual trend decreasing from 17.3% in 2016 to 13.3% in 2022 (-0.6%/year, r2 = .661). Those prescribed VK had greater rates of hepatic dysfunction (20.5% vs 3.1%), RBC transfusion (26.5% vs 11.2%), VTE (12.5% vs 4.6%), mortality (17.1% vs 4.4%), and median length of stay (16 [IQR: 8-33] vs 8 [4-15] days) (all P < .001). VK deficiency was diagnosed in 0.2% of encounters. Conclusions: In this multicenter retrospective cohort, VK prescribing was common among critically ill children diagnosed with sepsis. Phased trials are needed to demonstrate clinical efficacy and safety for VK in this population.

Post-bariatric pregnancy is associated with vitamin K1 deficiency, a case control study

BackgroundMaternal obesity is associated with adverse outcome for pregnancy and childbirths. While bariatric surgery may improve fertility and reduce the risk of certain pregnancy-related complications such as hypertension and gestational diabetes mellitus, there is a lack of evidence on the optimal nutritional monitoring and supplementation strategies in pregnancy following bariatric surgery. We aimed to assess the impact of bariatric surgery on micronutrients in post-bariatric pregnancy and possible differences between gastric bypass surgery and sleeve gastrectomy.MethodsIn this prospective case control study, we recruited 204 pregnant women (bariatric surgery n = 59 [gastric bypass surgery n = 26, sleeve gastrectomy n = 31, missing n = 2] and controls n = 145) from Akershus university hospital in Norway. Women with previous bariatric surgery were consecutively invited to study participation at referral to the clinic for morbid obesity and the controls were recruited from the routine ultrasound screening in gestational week 17–20. A clinical questionnaire was completed and blood samples were drawn at mean gestational week 20.4 (SD 4.5).ResultsThe women with bariatric surgery had a higher pre-pregnant BMI than controls (30.8 [SD 6.0] vs. 25.2 [5.4] kg/m2, p < 0.001). There were no differences between groups regarding maternal weight gain (bariatric surgery 13.3 kg (9.6) vs. control 14.8 kg (6.5), p = 0.228) or development of gestational diabetes (n = 3 [5%] vs. n = 7 [5%], p = 1.000). Mean levels of vitamin K1 was lower after bariatric surgery compared with controls (0.29 [0.35] vs. 0.61 [0.65] ng/mL, p < 0.001). Multiadjusted regression analyses revealed an inverse relationship between bariatric surgery and vitamin K1 (B -0.26 ng/mL [95% CI -0.51, -0.04], p = 0.047) with a fivefold increased risk of vitamin K1 deficiency in post-bariatric pregnancies compared with controls (OR 5.69 [1.05, 30.77] p = 0.044). Compared with sleeve gastrectomy, having a previous gastric bypass surgery was associated with higher risk of vitamin K1 deficiency (OR 17.1 [1.31, 223.3], p = 0.030).ConclusionPost-bariatric pregnancy is negatively associated with vitamin K1 with a higher risk of vitamin K1 deficiency in pregnancies after gastric bypass surgery compared with after sleeve gastrectomy. Vitamin K1 deficiency in post-bariatric pregnancy have potential risk of hypocoaguble state in mother and child and should be explored in future studies.

Clinical value of vitamin K testing in children aged 1-2 years with vitamin D deficiency rickets.

to investigate the clinical value of vitamin K testing in children with vitamin D deficiency rickets. fifty children with vitamin D deficiency rickets admitted to our hospital from March 2021 to March 2022 were recruited as the case group using convenience sampling; and an additional 50 children without bone health diseases during the same period of health checkup were selected as the control group. The relevant indexes between the two groups were compared. there were statistically significant differences between the two groups in the level of 25 hydroxyvitamin D3 [25-(OH)D3], the proportion of breastfeeding, and the proportion of preterm birth (p < 0.001). The levels of vitamin K1 and K2 were lower in the case group than in the control group, and the proportion of those with vitamin K1 deficiency and vitamin K2 deficiency were higher than the control group (p < 0.001) . Positive correlations were found between vitamins K1 and K2 and 25-(OH)D3, blood calcium, and blood phosphorus (p < 0.05); artificial feeding, preterm birth, vitamin K1 deficiency, and vitamin K2 deficiency were risk factors for the development of vitamin D deficiency rickets, and the highest AUC of the combination of each index in predicting the occurrence of vitamin D deficiency rickets was 0.951 (95 % CI: 0.910-0.991). preterm birth, artificial feeding, and vitamin K1 and K2 deficiency are independent risk factors for bone metabolism in children with vitamin D-deficiency rickets. And these risk factors have predictive and diagnostic value in the diagnosis and management of vitamin D deficiency rickets.

The Potential of Vitamin K as a Regulatory Factor of Bone Metabolism—A Review

Vitamin K (VK), a fat-soluble vitamin, is essential for the clotting of blood because of its role in the production of clotting factors in the liver. Moreover, researchers continue to explore the role of VK as an emerging novel bioactive molecule with the potential function of improving bone health. This review focuses on the effects of VK on bone health and related mechanisms, covering VK research history, homologous analogs, dietary sources, bioavailability, recommended intake, and deficiency. The information summarized here could contribute to the basic and clinical research on VK as a natural dietary additive and drug candidate for bone health. Future research is needed to extend the dietary VK database and explore the pharmacological safety of VK and factors affecting VK bioavailability to provide more support for the bone health benefits of VK through more clinical trials.

Recurrent subdural hematoma as presentation of neonatal biliary atresia: A case report

Biliary atresia is a congenital disorder of progressive and obliterative cholangiopathy, the most common cause of neonatal cholestasis, it can cause secondary vitamin-K deficiency bleeding due to the malabsorption of lipids and lipid-soluble vitamins due to cholestasis. We report a 46-day-old child presenting with cholestatic features complicated by subdural hematoma (SDH) and cerebral edema. On investigations, she was found to be having primary biliary atresia, for which she was operated but had a recurrence of the SDH on the opposite side.

Docking Complexes of Active Phytochemicals with VK-deficient Genes

Background:: Vitamin K (VK) deficiency occurs when the body does not have enough vitamin K to produce proteins that are essential for blood clotting and bone health. Vitamin K is a cofactor that plays a major role in various comorbidities. Over the years, efforts have been made to identify the interaction between natural compounds, such as K vitamers, that could play a sig-nificant role in regulation of the blood coagulation. We intended to obtain insights into the poten-tial therapeutic implications of phytochemicals for treating VK deficiency-related diseases by in-vestigating the interactions between phytochemicals and VK-deficient genes. Methods:: On active phytochemical docking complexes with VK-deficient genes, there is no spe-cific information available as of yet. In this computationally aided docking study, we were inter-ested in finding the pathogenic blood coagulation-related genes that are linked to VK deficiency. Based on literature reviews and databases, bioactive phytochemicals and other ligands were con-sidered. To provide precise predictions of ligand-protein interactions, docking parameters and scoring algorithms were thoroughly optimized. We have performed molecular docking studies and observed the way the complexes interact. Results:: Specific binding interactions between active phytochemicals and VK pathogenic muta-tions have been identified by the docking study. Hydrogen bonds, van der Waals interactions, and hydrophobic contacts, which are indications of high binding affinities, have been observed in the ligand-protein complexes. Few phytochemicals have demonstrated the ability to interact with the targets of VK-deficient genes, indicating their capacity to modify pathways relevant to VK defi-ciency. The results of the docking study have explained the three pathogenic genes, viz. VWF, F8, and CFTR, wherein VWF and F8 play important roles in blood coagulation and people with cyst-ic fibrosis, to have a deficiency in vitamin K. Thirty-five compounds from different plant and natural sources were screened through molecular docking, out of which two compounds have been considered as controls, including curcumin and warfarin (R-warfarin and S-warfarin), which are the most common anticoagulants readily available in the market. They act by inhibiting vita-min K epoxide reductase (VKOR), which is needed for the gamma-carboxylation of vitamin K-dependent factors. Conclusion:: A focus on other compounds, like theaflavin, ellagic acid, myricetin, and catechin was also made in this study as they show more binding affinity with the three pathogenic proteins. Based on the results, the complexes have been found to possess great potential and thus may be considered for further interaction studies. The potential for active phytochemicals to generate docking complexes with VK-deficient genes is highlighted in this computational analysis. Health disorders related to VK insufficiency may be significantly impacted by these interactions. To val-idate the expected interactions and determine the therapeutic potential of the identified phyto-chemicals, more experimental research, including in vitro and in vivo experiments, is needed.

Abstract B034: A scoping review of carcinogenic potential in prostate cancer from 40+ years of functional vitamin D and K deficiency

Abstract Introduction: Carcinogenesis is a form of accelerated genetic “Darwinian” evolution. Many cells start genetic change. Tobacco tar, an example of extensively researched carcinogen, demonstrates that it takes chronic exposure over 40+ years, accumulating mutations before death with multiple genetic events. Terminal acceleration often includes loss of major histocompatibility (MHC) antigens. Other co-carcinogens, genetic inheritance and chronic inflammation accelerates this process. Experiments, showing that malignant change induced in vitro is much faster than in vivo, suggest that other factors impact on the pace of malignant evolution. Two such factors (DNA repair and immune surveillance) are the best established. As considerable research is targeting DNA repair gene damage, this abstract focuses on latent immunity (less dependent on MHC system than T cell immunity) and its under-performance in carcinogenesis due to Vitamin D and K deficiency. Literature Review terms: Vitamin D(VD), Vitamin K(VK), Cancer, Carcinogenesis, Latent Immunity. Results: Three pieces of evidence that functional long-term VD and VK deficiency could have oncogenic potential were identified. The first was discovery that patients with chronic inflammation had hypermethylation of the VD receptor resulting in failure of the liver to convert stored VD into its active forms. Cancer patients with higher extent of methylation of VD receptor had worse clinical outcomes. Such deficiency is associated with reduced innate immunity due to macrophage dysfunction and this deficiency could increase microbiome dysbiosis. This suggestion is supported by studies linking PCa with 40+ years of persistent infection with the sun-sensitive microaerophilic bacterium Cutibacterium acnes and VD deficiency is linked with increased cancer but limited benefits in VD trials. The second observation is the demonstration that VK2 (Menaquinone) not VK1 (Phylloquinone) deficiency increased risk of PCa. These authors also showed that undercarboxylated osteocalcin, a biomarker of VK2 deficiency, was also linked with risk of PCa. The third observation was evidence from in-vitro breast cancer cell-line studies that Calcitriol plus K2 was synergistic in cytotoxicity assays. Measuring these effects, through the study of the biological age using methylation-based measures PhenoAge and GrimAge because of their relationship between biological aging and cancer, could be useful to monitor in future trials. Conclusions: Combined VD and VK studies have been found safe and beneficial in bone health. This limited review justifies further exploration of this combination in cancer patients. Using serial epigenetic clock scores is justified, given that these clocks are known to improve from diet and exercise interventions. Functional deficiency of VD and VK could be acting as co-carcinogens through enhanced inflammatory process, a precursor in many cancers including those without known carcinogen involvement such as PCa and also involved in accelerating tumour growth after primary treatment. Citation Format: Tim R.D. Oliver, Belinda Nedjai. A scoping review of carcinogenic potential in prostate cancer from 40+ years of functional vitamin D and K deficiency [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B034.

The Associations of Dietary Vitamin K Intake and Circulating Vitamin 25(OH)D with Serum Lipoprotein Levels: The Vitamin Deficiency Matters.

A synergistic interplay between vitamins K and D appears to exist. We aimed to investigate for the first time whether the associations of dietary vitamin K intake and circulating 25(OH)D with serum lipoprotein levels are influenced by the existence of deficiency of either or both vitamins K and D. Sixty individuals [24 males, 36(18-79) years old] were examined. Vitamin deficiency of K1 and D were defined as vitamin K1 intake/body weight (BW)<1.00 μg/kg/day and circulating 25(OH)D<20 ng/ml, respectively. In individuals with vitamin K1 deficiency, the vitamin K1 intake/BW correlated positively with high density lipoprotein-cholesterol (HDL-C) (r=0.509, p=0.008) and negatively with serum triglycerides (TG) (r=-0.638, p=0.001), whereas circulating 25(OH)D correlated negatively with TG (r=-0.609, p=0.001). In individuals with vitamin D deficiency, the vitamin K1 intake/BW correlated positively with HDL-C (r=0.533, p=0.001) and negatively with TG (r=-0.421, p=0.009), while circulating 25(OH)D correlated negatively with TG (r=-0.458, p=0.004). The above-mentioned associations of vitamin K1 intake/BW and circulating 25(OH)D with serum lipoproteins were not detected in individuals without vitamin K1 deficiency or the ones without vitamin D deficiency. The vitamin K2 intake/BW correlated negatively with low density lipoprotein-cholesterol (LDL-C) (r=-0.404, p=0.001). In conclusion, the associations of vitamin K1 intake with TG and HDL-C and of circulating 25(OH)D with TG were more pronounced in individuals with deficiency of either or both vitamins K1 and D. Increased dietary vitamin K2 intake was associated with decreased LDL-C.

Inferring bona fide Differentially Expressed Genes and Their Variants Associated with Vitamin K Deficiency Using a Systems Genetics Approach.

Systems genetics is key for integrating a large number of variants associated with diseases. Vitamin K (VK) is one of the scarcely studied disease conditions. In this work, we ascertained the differentially expressed genes (DEGs) and variants associated with individual subpopulations of VK disease phenotypes, viz., myocardial infarction, renal failure and prostate cancer. We sought to ask whether or not any DEGs harbor pathogenic variants common in these conditions, attempt to bridge the gap in finding characteristic biomarkers and discuss the role of long noncoding RNAs (lncRNAs) in the biogenesis of VK deficiencies.

Vitamin K-Dependent Carboxylation of Osteocalcin in Bone-Ally or Adversary of Bone Mineral Status in Rats with Experimental Chronic Kidney Disease?

Chronic kidney disease (CKD) commonly occurs with vitamin K (VK) deficiency and impaired bone mineralization. However, there are no data explaining the metabolism of endogenous VK and its role in bone mineralization in CKD. In this study, we measured serum levels of phylloquinone (VK1), menaquinone 4 and 7 (MK4, MK7), and VK-dependent proteins: osteocalcin, undercarboxylated osteocalcin (Glu-OC), and undercarboxylated matrix Gla protein (ucMGP). The carboxylated osteocalcin (Gla-OC), Glu-OC, and the expression of genes involved in VK cycle were determined in bone. The obtained results were juxtaposed with the bone mineral status of rats with CKD. The obtained results suggest that the reduced VK1 level observed in CKD rats may be caused by the accelerated conversion of VK1 to the form of menaquinones. The bone tissue possesses all enzymes, enabling the conversion of VK1 to menaquinones and VK recycling. However, in the course of CKD with hyperparathyroidism, the intensified osteoblastogenesis causes the generation of immature osteoblasts with impaired mineralization. The particular clinical significance seems to have a finding that serum osteocalcin and Glu-OC, commonly used biomarkers of VK deficiency, could be inappropriate in CKD conditions, whereas Gla-OC synthesized in bone appears to have an adverse impact on bone mineral status in this model.

Effect of Vitamin K on Bone Mineral Density and Fracture Risk in Adults: Systematic Review and Meta-Analysis.

Summary: Recent studies have proposed that adequate intake of Vitamin K (VK) is associated with a low risk of fracture and high bone mineral density (BMD) to improve skeletal health in adults. This systematic review was designed to summarize the most relevant and updated evidence discussing the relationship between VK and bone. It explores the effect of VK deficiency and its supplementation on various bone parameters. Methods: The distinct databases such as PubMed, the Cochrane Library, Google Scholar, National Clinical Trials, Current Controlled Trials, and Clinical Trials were searched up to Jan 2020 to identify eligible trials. All relevant randomized controlled trial studies with any oral dosage form of VK supplement administered for at least six months and assessing BMD or fracture in adults were extracted. Finally, two independent reviewers identified 20 relevant citations for the systematic review and extracted data in tabular form. Results: The meta-analysis was performed with all studies, including postmenopausal and osteoporotic females, for both total clinical and vertebral fracture outcomes. The quantitative analysis showed that the odds ratios (OR) of any fracture were lower for VK as compared to control [OR 0.42 (95% CI 0.27 to 0.66)] for vertebral fractures and OR of 0.44 (95% CI 0.23 to 0.88) for clinical fracture. For the BMD, a meta-analysis of the pooled effect of interventional studies suggested a non-significant association between the use of VK and improvement in femoral BMD (CI 95%, p = 0.08 [−0.03–0.20]). Conclusion: VK decreases general fracture risk, and it can be an option to counter bone loss disorders. However, insufficient evidence is available regarding the significant impact of VK on femoral neck BMD. Therefore, further studies are required to establish the therapeutic value of VK as a treatment for osteoporosis.

Biological Role of Vitamin K-With Particular Emphasis on Cardiovascular and Renal Aspects.

Vitamin K (VK) plays many important functions in the body. The most important of them include the contribution in calcium homeostasis and anticoagulation. Vascular calcification (VC) is one of the most important mechanisms of renal pathology. The most potent inhibitor of this process—matrix Gla protein (MGP) is VK-dependent. Chronic kidney disease (CKD) patients, both non-dialysed and hemodialysed, often have VK deficiency. Elevated uncarboxylated matrix Gla protein (ucMGP) levels indirectly reflected VK deficiency and are associated with a higher risk of cardiovascular events in these patients. It has been suggested that VK intake may reduce the VC and related cardiovascular risk. Vitamin K intake has been suggested to reduce VC and the associated cardiovascular risk. The role and possibility of VK supplementation as well as the impact of anticoagulation therapy on VK deficiency in CKD patients is discussed.

Vitamin K Deficiency in the Setting of Blenderized Tube Feeding Regimen in a Teenager: A Case Report

Vitamin K acts a cofactor for the gamma-carboxylation of several proteins in the coagulation cascade. The clinical spectrum of vitamin K deficiency (VKD) can be asymptomatic to a significant bleeding. VKD is classically seen in newborns. However, this can manifest later in patients with risks such as sub-optimal nutrition, fat malabsorption, medications including antibiotics. A 17-year-old male with spinal muscular atrophy (SMA) Type 1, tracheostomy with ventilator dependent, gastrostomy tube feeding was seen by the gastroenterologist following treatment for small intestinal bacterial overgrowth (SIBO). Investigations showed coagulopathy following which he was transferred to the Pediatric ICU. Labs revealed prothrombin time (PT) 114 s [Normal 9.4–12.5 s], INR (International normalized ratio) 12.6 [Normal < 1.1] and partial thromboplastin time (PTT) 90 s [Normal 25.1–36.5 s]. Mixing studies and coagulation assays were consistent with VKD (low Factor VII and Factor IX with normal Factor V). His home blenderized feeding regimen met the caloric requirement but not the adequate intake (AI) values for vitamin K and other minerals. He received intravenous vitamin K (phytonadione) for five consecutive days with resolution of the coagulopathy (PT 13.2 s, PTT 37.1 s, INR 1.2). The patient was discharged on enteral vitamin K and additional supplements following dietary review by a nutritionist. Clinicians should be cognizant of VKD in patients on blenderized tube feeds which may not meet the adequate intake (AI) goals. In patients who are not receiving nutritionally complete formulas or receiving inadequate volumes, it is important to monitor macro and micronutrients.

Role of Vitamin K in Intestinal Health.

Intestinal diseases, such as inflammatory bowel diseases (IBDs) and colorectal cancer (CRC) generally characterized by clinical symptoms, including malabsorption, intestinal dysfunction, injury, and microbiome imbalance, as well as certain secondary intestinal disease complications, continue to be serious public health problems worldwide. The role of vitamin K (VK) on intestinal health has drawn growing interest in recent years. In addition to its role in blood coagulation and bone health, several investigations continue to explore the role of VK as an emerging novel biological compound with the potential function of improving intestinal health. This study aims to present a thorough review on the bacterial sources, intestinal absorption, uptake of VK, and VK deficiency in patients with intestinal diseases, with emphasis on the effect of VK supplementation on immunity, anti-inflammation, intestinal microbes and its metabolites, antioxidation, and coagulation, and promoting epithelial development. Besides, VK-dependent proteins (VKDPs) are another crucial mechanism for VK to exert a gastroprotection role for their functions of anti-inflammation, immunomodulation, and anti-tumorigenesis. In summary, published studies preliminarily show that VK presents a beneficial effect on intestinal health and may be used as a therapeutic drug to prevent/treat intestinal diseases, but the specific mechanism of VK in intestinal health has yet to be elucidated.

Genetic spectrum and clinical characteristics of 3\u03b2-hydroxy-\u03945-C27-steroid oxidoreductase (HSD3B7) deficiency in China

BackgroundBiallelic variants in HSD3B7 cause 3β-hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7) deficiency, a life-threatening but treatable liver disease. The goal of this study was to obtain detailed information on the correlation between the genotype and phenotype of HSD3B7 deficiency and to report on responses to primary bile acid therapy.MethodsThe medical records of a cohort of 39 unrelated patients with genetically and biochemically confirmed HSD3B7 deficiency were examined to determine whether there exist genotype-phenotype relationships in this bile acid synthesis disorder.ResultsIn all, 34 of the 44 variants identified in HSD3B7 were novel. A total of 32 patients presented early with neonatal cholestasis, and 7 presented after 1-year of age with liver failure (n = 1), liver cirrhosis (n = 3), cholestasis (n = 1), renal cysts and abnormal liver biochemistries (n = 1), and coagulopathy from vitamin K1 deficiency and abnormal liver biochemistries (n = 1). Renal lesions, including renal cysts, renal stones, calcium deposition and renal enlargement were observed in 10 of 35 patients. Thirty-three patients were treated with oral chenodeoxycholic acid (CDCA) resulting in normalization of liver biochemistries in 24, while 2 showed a significant clinical improvement, and 7 underwent liver transplantation or died. Remarkably, renal lesions in 6 patients resolved after CDCA treatment, or liver transplantation. There were no significant correlations between genotype and clinical outcomes.ConclusionsIn what is the largest cohort of patients with HSD3B7 deficiency thus far studied, renal lesions were a notable clinical feature of HSD3B7 deficiency and these were resolved with suppression of atypical bile acids by oral CDCA administration.

PIVKA II як показник дефіциту вітаміну К у дітей перших місяців життя, які отримують виключно грудне вигодовування Українське дослідження

Актуальність. Новонароджені та діти перших місяців життя, особливо ті, які знаходяться на грудному вигодовуванні, природним чином схильні до дефіциту вітаміну К. Метою нашого дослідження було уточнення частоти виявлення дітей перших шести місяців життя української популяції, які знаходяться виключно на грудному вигодовуванні, із підвищеними концентраціями protein induced by vitamin K absence (PIVKA II) для вивчення сучасних умов формування дефіциту вітаміну К. Матеріали та методи. Об’єктом дослідження стали зразки донорської сироватки 180 дітей віком від 1 доби до 6 місяців, які народилися в строк із масою тіла від 2800 до 4200 г і оцінкою за шкалою Апгар 7–10 балів. Усі діти перебували на грудному вигодовуванні з моменту народження. Результати. Як показали наші спостереження, вітамін-К-дефіцитний стан відмічається в більше ніж 50 % новонароджених за даними виявлення позитивного тесту ELISA, що вказує на недостатній рівень карбоксильованого протромбіну (PIVKA II) у сироватці крові. Найбільше число позитивних за тестом PIVKA II немовлят відмічається в ранній неонатальний період, що свідчить про те, що гіповітаміноз формується внутрішньоутробно. Висновки. Забезпеченість вітамінами групи К, необхідними для синтезу цілого ряду незамінних протеїнів організму дитини, у більше ніж половини здорових народжених у строк новонароджених субпопуляції півдня України недостатня. Причинами цього явища є ідіопатичні внутрішньоутробні фактори, невиконання профілактичної ін’єкції вітаміну К після народження, виключно грудне вигодовування, дефіцитне за філо- та меноквінонами, а також порушення стану товстокишкового мікробіоценозу бактерій, що важливо для створення пулу ендогенних меноквінонів, які забезпечують подолання вітаміндефіцитного стану в ранньому дитинстві.

Kidney Function-Dependence of Vitamin K-Status Parameters: Results from the TransplantLines Biobank and Cohort Studies.

High circulating dephosphorylated (dp) uncarboxylated (uc) matrix Gla protein (MGP) and uc osteocalcin (OC) concentrations are regarded as markers of vitamin K-deficiency. However, because MGP and OC are small molecules, they may potentially pass the glomerulus, and their blood concentrations may strongly depend on kidney function. However, many studies with vitamin K-status parameters do not structurally adjust for baseline kidney function, and detailed studies on kidney function-dependence of vitamin K-status markers are lacking. We therefore measured plasma dp-ucMGP using a chemiluminescent assay in 578 kidney transplant recipients (41% females, age 56 ± 13y, 7.5 (3.2 to 13.7)y after transplantation, eGFR 49 ± 17 mL/min/1.73 m2) participating in the prospective TransplantLines Cohort Studies. Additionally, dp-carboxylated MGP, ucOC and carboxylated OC were measured using ELISA in plasma of a subgroup of 60 participants. Finally, dp-ucMGP was measured in a separate cohort of 124 kidney transplant recipients before and three months after kidney transplantation. Dp-ucMGP positively correlated with creatinine, cystatin C, and negatively with eGFR (Spearman’s ρ 0.54, 0.60, and −0.54, respectively, p < 0.001 for all), and each 10 mL/min/1.73 m2 increase in eGFR was associated with a 14.0% lower dp-ucMGP. Additionally, dp-ucMGP strongly declined after kidney transplantation (pretransplantation: 1252 (868 to 1744) pmol/L to posttransplantation: 609 (451 to 914) pmol/L, p < 0.001). Proportions of dp-ucMGP over total MGP and ucOC over total OC were not associated with eGFR. This study highlights that dp-ucMGP is strongly associated with kidney function, and that levels strongly decrease after kidney transplantation. We therefore propose adequate adjustment for kidney function, or the use of kidney function-independent parameters such as proportion of uncarboxylated MGP or OC in the assessment of vitamin K-status in clinical practice and research.

The Role of Vitamin K in Cholestatic Liver Disease.

Vitamin K (VK) is a ligand of the pregnane X receptor (PXR), which plays a critical role in the detoxification of xenobiotics and metabolism of bile acids. VK1 may reduce the risk of death in patients with chronic liver failure. VK deficiency is associated with intrahepatic cholestasis, and is already being used as a drug for cholestasis-induced liver fibrosis in China. In Japan, to treat osteoporosis in patients with primary biliary cholangitis, VK2 formulations are prescribed, along with vitamin D3. Animal studies have revealed that after bile duct ligation-induced cholestasis, PXR knockout mice manifested more hepatic damage than wild-type mice. Ligand-mediated activation of PXR improves biochemical parameters. Rifampicin is a well-known human PXR ligand that has been used to treat intractable pruritus in severe cholestasis. In addition to its anti-cholestatic properties, PXR has anti-fibrotic and anti-inflammatory effects. However, because of the scarcity of animal studies, the mechanism of the effect of VK on cholestasis-related liver disease has not yet been revealed. Moreover, the application of VK in cholestasis-related diseases is controversial. Considering this background, the present review focuses on the effect of VK in cholestasis-related diseases, emphasizing its function as a modulator of PXR.

Experimental Model of Subclinical Vitamin K Deficiency.

Vitamin K (VK) is a co-factor in the post-translational gamma glutamic carboxylation of Gla-proteins. VK-dependent coagulation factors are carboxylated in the liver by VK1. Osteocalcin and Matrix-Gla protein (MGP) are carboxylated in extrahepatic tissues by VK2. A model of VK deficiency would be suitable for studying extrahepatic Gla-proteins provided that severe bleeding is prevented. The aim of this work was to adapt an established protocol of vascular calcification by warfarin-induced inactivation of MGP as a calcification inhibitor, in an attempt to create a broader state of subclinical VK deficiency and to verify its safety. Two consecutive experiments, each lasting 4 weeks, were required to modify the dosing schedule of warfa-rin and VK1 and to adapt it to the Wistar rats used. The original high doses of warfarin used initially had to be halved and the protective dose of VK1 to be doubled, in order to avoid treatment-induced hemorrhagic deaths. The second experiment aimed to confirm the efficacy and safety of the modified doses. To verify the VK deficiency, blood vessels were examined histologically for calcium deposits and serum osteocalcin levels were mea-sured. The original dosing schedule induced VK deficiency, manifested by arterial calcifications and dramatic changes in carboxyl-ated and uncarboxylated osteocalcin. The modified dosing regimen caused similar vascular calcification and no bleeding. The modified protocol of carefully balanced warfarin and VK1 doses is an effective and safe way to induce subclinical VK deficiency that can be implemented to investigate VK-dependent proteins like osteocalcin.