Assessment of Oral Anticoagulation with Vitamin K Antagonists in Patients Living in a Low-Income Country of West Africa

Introduction: Despite the rise of direct oral anticoagulants (DOACs), vitamin K antagonists (VKA) remain the most widely used oral anticoagulants in developing countries. The aim of this study was to estimate the prevalence of good anticoagulation in patients treated with VKA in Lomé and describe associated factors. Methods: This was a cross-sectional study conducted from November 2019 to October 2020 in the cardiology departments of two University teaching hospitals in Lomé (CHU Sylvanus Olympio and CHU Campus), involving patients on VKA for ≥3 months, with a target international normalized ratio (INR) of 2.5 and a therapeutic margin between 2 and 3. The quality of anticoagulation was assessed by the time in therapeutic range (TTR) which was assessed by the Rosendaal method. Good anticoagulation was defined by a TTR > 70%. Results: A total of 344 patients were included (mean age = 58 ± 13.8 years, women = 56.1%). Indications for VKA treatment were represented by venous thromboembolic disease (43.3%), supraventricular arrhythmia (28.2%), severe left ventricular systolic dysfunction (19.8%) and pulmonary hypertension (8.7%). The average TTR was 47.6 ± 20.8%. The rate of good anticoagulation was 17.7%. Factors associated with good anticoagulation were the use of fluindione vs acenocoumarol (OR = 11.17;95% CI: 3.2 - 39.6;p = 0.0002), concomitant low-dose aspirin (OR 4.44;95% CI: 1.4 - 13.9;p = 0.01) and INR monitoring exclusively by the patient himself (OR = 4.92;95% CI: 1.5 - 16.3;p = 0.008). The rate of thromboembolic and hemorrhagic complications was each 2.6% and was not correlated with the quality of anticoagulation. Quality of anticoagulation by VKAs was poor in our practice. Factors associated with good anticoagulation were the use of fluindione vs acenocoumarol, concomitant low-dose aspirin and monitoring of INR exclusively by the patient himself. Conclusion: The quality of oral anticoagulation by VKAs could be improved in our practice by the creation of anticoagulation clinics for better therapeutic education of patients and efficient management of VKA dose, and the use of prescription assistance software.

Dietary Vitamin K Restriction and Effectiveness of Vitamin K Antagonists Prescribed at the CNHU-HKM University Cardiology Clinic/BENIN

Introduction: Their efficacy in preventing thrombotic and embolic events has been proven in numerous studies, but their narrow therapeutic index requires particular vigilance, especially in terms of biology. In addition, treatment-related hemorrhagic complications are not uncommon. This study explores the influence of dietary vitamin K restriction on the efficacy of antivitamin K treatment at the University Cardiology Clinic of CNHU-HKM. Methods: Cross-sectional and descriptive study that took place from 25 April to 29 August 2019. Patients’ dietary behaviors and successive INR values were collected. Information on dietary intake was obtained by 2 non-consecutive 24-hour recalls. The effectiveness of VKA treatment was assessed by the “Time in Therapeutic Range” (TTR) of the INR. VKA treatment was considered effective for a TTR greater than 65%. Results: At the end of this study, 40 patients were surveyed. The mean age of the participants was 58.05 years ± 13.32 years, with a sex ratio of 1.35. Complete arrhythmia due to atrial fibrillation was the main indication for VKA treatment (37.50%) and fluindione was the most commonly prescribed drug (77.50%). The duration of treatment was less than or equal to 2 years in 47.5% of the subjects surveyed. Before starting treatment, 85% of patients received advice on restricting vitamin K-rich foods, and 45% of patients reported “food burnout” after a period of compliance with the restriction. The majority of respondents (97.50%) complied with the restriction on vitamin K-rich foods. All respondents had high energy intakes and a poor distribution of macronutrients, with a predominance of carbohydrates and proteins. 2.5% of respondents were on effective anti-vitamin K therapy with a TTR of over 65%. Conclusion: Restriction of vitamin K-rich foods is not conducive to effective treatment with vitamin K antagonists.

Decreased Expression of Vitamin K Epoxide Reductase Complex Subunit 1 in Kidney of Patients with Calcium Oxalate Urolithiasis

Urinary prothrombin fragment 1 （UPTFl） is a potent inhibitor of urinary stone formation. UPTF1 exerts such inhibitory effect by effective 7-carboxylation in which vitamin K epoxide reductase complex subunit 1 （VKORC1）, the rate-limiting enzyme, is involved. This study examined the correlation between VKORC1 expression and calcium oxalate urolithiasis. The renal cortex samples were obtained from patients undergoing nephrectomy and then divided into 3 groups： urolithiasis group, control group A [hydronephrosis-without-stone （HWS） group], control group B （normal control group）, The localization and expression of VKORC1 in renal tissues were determined by using immunohistochemistry, immunofluorescence microscopy, Western blotting and SYBR Green I real-time reverse-transcription PCR. The rapid amplification of cDNA ends （RACE） were conducted to obtain the 3＇- and 5＇-untranslated region （UTR） of VKORC1. The results showed that VKORC1 was located in the cytoplasm of renal tubular epithelial cells. The expression of VKORC1 in the uro- lithiasis group was significantly lower than that in the other two control groups （P〈0.05）. Moreover, the 3＇- and 5＇-UTR sequence of the VKORC1 gene was successfully cloned. No insertion or deletion was found in the 3＇- and 5＇-UTR. However, a 171-bp new base sequence was discovered in the up- stream of 5＇-UTR end in the urolithiasis group. It was concluded that the decreased expression of VKORC 1 may contribute to the development of calcium oxalate urolithiasis in the kidney.

Protein induced by vitamin K absence or antagonist-Ⅱ versus alpha-fetoprotein in the diagnosis of hepatocellular carcinoma: A systematic review with meta-analysis

Background: As a promising biomarker of hepatocellular carcinoma(HCC), protein induced by vitamin K absence or antagonist-Ⅱ(PIVKA-Ⅱ) has been studied extensively. However, its diagnostic capability varies across HCC studies. This study aimed to compare the performance of PIVKA-Ⅱ with alpha-fetoprotein(AFP) in the diagnosis of HCC. Data sources: A systematic literature search was conducted to identify the studies from MEDLINE, Embase and Cochrane Library Databases, which were published up to December 20, 2017 to compare the diagnostic capability of PIVKA-Ⅱ and AFP for HCC. The data were pooled using random effects model. Pooled sensitivity and specificity were calculated. Summary receiver operating characteristic curve(ROC) was employed to evaluate the diagnostic accuracy of each marker. Results: Thirty-one studies were included. The pooled sensitivity(95% CI) of PIVKA-Ⅱ and AFP was 0.66(0.65–0.68) and 0.66(0.65–0.67), respectively in diagnosis of HCC; and the corresponding pooled specificity(95% CI) was 0.89(0.88–0.90) and 0.84(0.83–0.85), respectively. The area under the ROC curve(AUC) of PIVKA-Ⅱ and AFP was 0.856(0.817–0.895) and 0.770(0.728–0.811), respectively. Subgroup analysis showed that PIVKA-Ⅱ was superior to AFP in terms of the AUC for both small HCC( < 3 cm) [0.863(0.825–0.901) vs 0.717(0.658–0.776)] and large HCC( ≥ 3 cm) [0.854(0.811–0.897) vs 0.729(0.682–0.776)]; for American [0.926(0.897–0.955) vs 0.698(0.594–0.662)], European [0.772(0.743–0.801) vs 0.628(0.594–0.662)], Asian [0.838(0.812–0.864) vs 0.785(0.764–0.806)] and African [0.812(0.794–0.840) vs 0.721(0.675–0.767)] HCC patients; and for HBV-related [0.909(0.866–0.951) vs 0.714(0.673–0.755)] and mixed-etiology [0.847(0.821–0.873) vs 0.794(0.772–0.816)] HCC. Conclusion: This meta-analysis indicates that PIVKA-Ⅱ is better than AFP in terms of the accuracy for diagnosing HCC, regardless of tumor size, patient ethnic group, or HCC etiology.

Relationship between Acquired Deficiency of Vitamin K-dependent Clotting Factors And Hemorrhage

This study examined the changes of activities of vitamin K-dependent clotting factors(VKDCF) under various pathological conditions and explored the relationship between acquired deficiency of VKDCFs and hemorrhage.Clinical data of 35 patients who were diagnosed as having acquired deficiency of VKDCF were retrospectively analyzed.Coagulation factors involved in the intrinsic and extrinsic pathways were detected in these patients and 41 control subjects.The results showed that the average activities of VKDCFs were decreased in the patients in comparison to the control subjects and significantly increased after treatment of these patients with vitamin K and blood products.Multivariate regression analysis indicated that decreased activity of VKDCF was not an independent risk factor for bleeding disorders owing to deficiency or metabolic disturbance of vitamin K.It was concluded that acquired deficiency of VKDCF occurs under a variety of pathologic conditions and is closely associated with hemorrhagic events.Administration of vitamin K and transfusion of blood products containing high concentrations of VKDCFs helps alleviate the hemorrhagic diseases.

Analysis of Vitamin K_3 by a Fluorescent Spectroelectrochemistry Method

A simple and sensitive spectroelectrochemistry method for the determination of vitamin K3 was developed by combining electrolysis and fluoremetry. This method was based on that vitamin K3 was reduced at a glassy carbon electrode, and its product with characteristic fluorescence at 420 nm was determined with excitation wavelength at 309 nm. Under optimized electrochemical reaction conditions and fluorescent experiment parameters, the fluorescence intensity was proportional to the concentration of vitamin K3 in a range from 3.50×10^-7 to 1.05×10^-5 mol/L with a correlation coefficient of 0.9991, and detection limit was estimated to be 7.50× 10^-8 mol/L at a signal/noise ra- tio of 3. The relative standard deviation was less than 4.3%（n=5） and the recovery was in a range of 97%-105% for the determination of vitamin K3 in pharmaceutical preparations. The result is satisfactory for the determination of vitamin K3 as comparison to that from HPLC method.

Improvement of Vitamin K_2 Production by Escherichia sp.with Nitrogen Ion Beam Implantation Induction

Low-energy ion implantation as a novel mutagen has been increasingly applied in the microbial mutagenesis for its higher mutation frequency and wider mutation spectra. In this work, N^＋ ion beam implantation was used to enhance Escherichia sp. in vitamin K2 yield. Optimization of process parameters under submerged fermentation was carried out to improve the vitamin K2 yield of mutant FM5-632. The results indicate that an excellent mutant FM5-632 with a yield of 123.2±1.6 μg/L, that is four times that of the original strain, was achieved by eight successive implantations under the conditions of 15 keV and 60 ×2.6 ×10^13 ions/cm^2. A further optimization increased the yield of the mutant by 39.7%, i.e. 172.1±1.2 μg/L which occurred in the mutant cultivated in the optimal fermentation culture medium composed of （per liter）： 15.31 g glycerol, 10 g peptone, 2.89 g yeast extract, 5 g K2HPO4, 1 g NaCl, 0.5 g MgSO4·7H2O and 0.04 g cedar wood oil, incubated at 33 ℃, pH 7.0 and 180 rpm for 120 h.

Genetic Mutation of Vitamin K-dependent Gamma-glutamyl Carboxylase Domain in Patients with Calcium Oxalate Urolithiasis

To investigate the exon mutation of vitamin K-dependent gamma-glutamyl carboxylase （GGCX or VKDC） in patients with calcium oxalate urolithasis, renal cortex and peripheral blood samples were obtained from severe hydronephrosis patients （with or without calculi）, and renal tumor patients undergoing nephrectomy. GGCX mutations in all 15 exons were examined in 44 patients with calcium oxalate urolithiasis （COU） by polymerase chain reaction （PCR） and denatured high pressure liquid chromatography （DHPLC）, and confirmed by sequencing. Mutation was not found in all COU samples compared to the controls. These data demonstrated that functional GGCX mutations in all 15 exons do not occur in most COU patients. It was suggested that there may be no significant association between the low activity and mutation of GGCX in COU.

Vitamin K脉冲辐解与激光光解的研究(Ⅰ)──VK_3水溶液脉冲辐解还原反应时间分辨的研究

研究了VK3水溶液经脉冲辐解后VK3阴离子自由基的形成机理及其次级反应，观察到VK3阴离子自由基的最大吸收波长位于约340nm处，这与VK3阴离子自由基最大吸收波长在390nm附近的观点有所不同，并初步分析了这种差异的原因．初步探讨了VK3对Thymine-和Adenine-的修复作用，显示VK3本身是很好的辐射保护剂．

Vitamin K脉冲辐解与激光光解的研究(Ⅱ)——VK_3水溶液氧化反应时间分辨的研究

ＶｉｔａｍｉｎＫ３（ＶＫ３）是很好的电子载体，文献［１，２］利用微秒级脉冲辐解研究了ＶＫ３水溶液体系，测定了一些自由基与ＶＫ３进行的单电子氧化还原反应及相关动力学参数．我们［３］曾用选定的还原性活性粒子，通过脉冲辐解动态吸收光谱法研究了ＶＫ３水溶液的...

The risk of bleeding of triple therapy with vitamin K-antagonists,aspirin and clopidogrel after coronary stent implantation:Facts and questions

Background Triple therapy(TT)with vitamin K-antagonists(VKA),aspirin and clopidogrel is the recommended antithrombotic treatment following percutaneous coronary intervention with stent implantation(PCI-S)in patients with an indication for oral anticoagulation.TT is associated with an increased risk of bleeding,but available evidence is flawed by important limitations,including the limited size and the retrospective design of most of the studies,as well as the rare reporting of the incidence of in-hospital bleeding and the treatment which was actually ongoing at the time of bleeding.Since the perceived high bleeding risk of TT may deny patients effective strategies,the determination of the true safety profile of TT is of paramount importance.Methods All the 27 published studies where the incidence of bleeding at various time points during follow-up has been reported separately for patients on TT were reviewed,and the weakness of the data was analyzed.Results The absolute incidence of major bleeding upon discharge at in-hospital,≤1 month,6 months,12 months and≥12 months was:3.3%±1.9%,5.1%±6.7%,8.0%±5.2%,9.0%±8.0,and 6.2%±7.8%,respectively,and not substantially different from that observed in previous studies with prolonged dual antiplatelet treatment with aspirin and clopidogrel.Conclusions While waiting for the ongoing,large-scale,registries and clinical trials to clarify the few facts and to answer the many questions regarding the risk of bleeding of TT,this treatment should not be denied to patients with an indication for VKA undergoing PCI-S provided that the proper measures and cautions are implemented.

Vitamin K alleviates bone calcium loss caused by Salmonella Enteritidis through carboxylation of osteocalcin

Background:The present study aimed at evaluating the effect of vitamin K(VK)supplementation on bone health of laying hens challenged by Salmonella Enteritidis.Methods:A total of 8032-week-old double negative salmonella-free brown-egg laying hens were randomly assigned to 4 treatments with 20 replicates each(1 bird per replicate)according to a 2×2 factorial design with 2 dietary VK supplementation levels[0 mg/kg(VK0)vs 2 mg/kg VK(VK2)and 2 challenge treatments[Salmonella Enteritidis(SE)vs physiological saline solution(PS)].During the last 3 days of week 43 of age,birds of both VK treatments were either orally challenged with 1.0 mL suspension of 109 cfu/mL S.Enteritidis daily or received the same volume of PS.Results:The laying rate,daily egg mass,tibia strength,CT,cOC and cOC/(cOC+ucOC)of VK2 treatment increased(P<0.05)in contrast to VK0,however,the medullary area and ucOC of VK2 treatment decreased(P<0.05)in contrast to VK0.Mortality,medullary area,serum Ca content of SE treatments increased(P<0.05)in contrast to PS treatments.In both SE treatments,the decrease(P<0.05)in birds’tibia strength was associated with higher(P<0.05)Ca levels in serum.There is an interaction(P<0.05)between SE challenge and VK levels with regard to tibia strength and serum Ca levels.At week 42,serum CT was positively correlated with cOC(R=0.99,P=0.009);at week 44,tibia strength was positively correlated with BMD(R=0.95,P=0.045),but negatively correlated with medullary area(R=−0.98,P=0.018).Conclusions:VK(2 mg/kg)supplementation to diets of laying hens can enhance bone strength under challenge situations with Salmonella Enteritidis.Medullary area has proven to be a sensitive biomarker for bone calcium loss caused by SE infection.

Clinical Study of Vitamin K_3 Acupoint Injection In Treating Pelvic Pain

Pelvic pain is one of the most common symptoms in gynecologic outpatients. Primary dysmenorrhea, acute or chronic pelvic inflammatory disease, endometriosis, post-operational pelvic adhesion, blood stagnation of pelvic vein, etc. , are mentioned as the often encountered causes of pelvic pain. It has been reported in the recent ten or more years that intramuscular injection of vitamin K3 (Vit K3) could relieve pain induced by smooth muscle spasm. In order to evaluate the effect of Vit K3 administered by acupoint injection in relieving pelvic pain, 180 patients were treated and observed from April 1997 to April 1999 in our hospital, and good therapeutic effect was obtained. It was reported as follows.

Cutaneous allergic reaction to subcutaneous vitamin K_(1):A case report and review of literature

BACKGROUND Vitamin K1(phytomenadione)is a fat-soluble naturally occurring vitamin that is widely used to treat certain coagulation disorders.Adverse cutaneous reactions to vitamin K1 can occur;however,owing to its low incidence and considerable variability in presentation and morphology,its diagnosis can be easily overlooked.Managing these reactions may be challenging for patients and clinicians.Therefore,reviewing the adverse cutaneous reactions to vitamin K1 is important.CASE SUMMARY Here we report the case of a 50-year-old woman with no pre-existing hepatic disease who developed a cutaneous allergic reaction to subcutaneous vitamin K1 that presented as localized eczematous plaques at the vitamin K1 injection site.The eruption developed within 5 d of the injection and persisted for 32 mo despite treatment with topical and intralesional steroids.Eczema was diagnosed based on the results of the pathological examination,immunohistochemical staining,and a skin biopsy.The patient was advised to take herbal medicines orally twice daily.After treatment and follow-up,the patient’s eczematous urticarial plaques improved and her condition stabilized.CONCLUSION Here we present the first case of a cutaneous allergic reaction to subcutaneous vitamin K1 that was successfully treated with Chinese medicine.

CT examination, clinical situation and experimental characteristics of infants with intracranial hemorrhage induced by delayed vitamin K deficiency

BACKGROUND: Delayed vitamin K deficiency is characterized by acute onset, severe illness and high fatality rate. 33%-50% survivors accompany with other various nervous system sequelas. Therefore, diagnosis and treatment of intracranial hemorrhage in time become a key factor for improving healing rate and reducing fatality rate and incidence of sequela. OBJECTIVE: To investigate the clinical situation, experimental characteristics, CT examination and terminative characteristics of infants with intracranial hemorrhage induced by delayed vitamin K deficiency. DESIGN: Case analysis. SETTING: Department of Pediatrics, Zhongshan Hospital Affiliated to Xiamen University. PARTICIPANTS: A total of 17 infants with intracranial hemorrhage induced by delayed vitamin K deficiency aged 1-3 months including 11 boys and 6 girls were selected from Department of Pediatrics, Zhongshan Hospital Affiliated to Xiamen University from January 1994 to December 2005. All infants had drowsiness, rejective milk, spiting milk, gaze of both eyes, tic, coma, full anterior fontanelle, high muscular tension and cerebral hernia, etc. Experimental examination demonstrated that infants had anemia at various degrees; prothrombin time and partial thromboplastin time were prolonged; platelet count was normal. CT examination indicated that screenages of subarachnoid hemorrhage, subdural hematoma, cerebral parenchyma hemorrhage and intraventricular hemorrage were changed. Hemorrhage was stopped by the application of vitamin K. All patients provided informed consent. METHODS: ① Clinical situation and physical sign of infants were observed after hospitalization and scanned with rapid spiral CT scanning system. The thickness and average space of layers were 8-10 mm and the scanning time was 5 s with window width of 30-80 Hu and window position of 28-35 Hu. ② After hospitalization, four items of blood coagulation was measured with Futura meter and biochemical indexes of blood, such as serum calcium, serum alkaline phosphatase, total bilirubin, direct bilirubin and indirect bilirubin, were detected with Roche Modular PPI automatic biochemistry analyzer. ③ After hospitalization, infants were given 5-10 mg vitamin K1 for 3-5 days, and then, they were transfused with 10-15 mL/kg fresh plasma or whole blood for 1-3 times and received other relative therapies. Therapeutic effects were evaluated based on clinical diagnosis and criteria. MAIN OUTCOME MEASURES: ① Clinical situation, physical sign and CT examination; ② results of experimental examination; ③ treatment and termination. RESULTS: A total of 17 infants with intracranial hemorrhage were involved in the final analysis. ① Clinical situation, physical sign and CT examination: All infants had pale facial expression and full or bossing anterior fontanelle. Among them, 13 infants had drowsiness or dysphoria, 12 rejective milk or emesis, 11 tic, 13 injection site hemorrhage, 2 gastrointestinal hemorrhage, 3 cerebral hernia, 11 high muscular tension and 6 cervical rigidity. CT examination demonstrated that most infants (88%, 15/17) had subarachnoid hemorrhage; 10 (59%, 10/17) had subdural hematoma; 8 (47%, 8/17) had cerebral parenchyma hemorrhage; few had intraventricular hemorrhage. In addition, results of CT examination also indicated that 17 infants had intracranial hemorrhage. Hemorrhage sites of 12 infants were equal to or more than 2, which was accounted for 70% (12/17); meanwhile, partial cases accompanied with a large area of focus of cerebral infarction or cerebral hypoxia-ischemia lesion. ② Results of experimental examination: There were 6 infants with elongation of prothrombin time, 5 with partial elongation of prothrombin time, 4 with decrease of serum calcium (1.69-2.25 mmol/L), 3 with increase of serum alkaline phosphatase, 3 with increase of total bilirubin, 3 with increase of direct bilirubin, and 3 with increase of indirect bilirubin. ③ Treatment and termination: After treatment, 12 infants were cured well, 3 improved, 1 given up and 1 died. Later, ten infants received CT re-examination at 3 months after treatment. The results indicated that 3 infants had simple subarachnoid hemorrhage and 4 had subarachnoid hemorrhage accompanying with subdural hematoma. Their focuses were absorbed well and not show as obvious sequela. One infant had subdural hematoma accompanying with subarachnoid hemorrhage, cerebral parenchyma hemorrhage, intraventricular hemorrage and cerebral hypoxia ischemia, and then, after hematom absorption, obvious cerebral malacia focus, hydrocephalus, brain atrophy and inferior accumulating fluid of dura mater were observed; 2 had subdural hematoma accompanying with subarachnoid hemorrhage and cerebral hypoxia ischemia, and then, after bleeding absorption, brain atrophy was changed remarkably; changes of hydrocephalus were observed in one infant. CONCLUSION: ① Symptoms of pale facial expression, full or bossing anterior fontanelle, drowsiness and dysphoria are observed in infants with delayed vitamin K deficiency . ② Experimental indexes demonstrate that prothrombin time and partial prothrombin time are prolonged, and numbers of infants having decrease of serum calcium are in the third place. ③ Poly-intracranial hemorrhage is a notable characteristic of CT examination. Partial infants who have poly-intracranial hemorrhage always accompany with cerebral hypoxia-ischemia lesion or cerebral infarction. Clinical situation and prognosis of infants who have a large area of intracranial hemorrhage and cerebral hypoxia-ischemia changes are poor; however, those of infants who have simple subarachnoid hemorrhage or combination of subarachnoid hemorrhage with subdural hematoma are well. ④ Effect of vitamin K on this kind of disease is well.

Diagnostic value of gamma-glutamyltransferase/aspartate aminotransferase ratio, protein induced by vitamin K absence or antagonist II, and alpha-fetoprotein in hepatitis B virus-related hepatocellular carcinoma

BACKGROUND Researchers have investigated the diagnostic value of protein induced by vitamin K absence or antagonist II (PIVKA-II) and alpha-fetoprotein (AFP) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), and obtained abundant clinical diagnostic data. However, PIVKA-II and AFP have unsatisfactory specificity and sensitivity in the diagnosis of early-stage HBV-related HCC. Gamma-glutamyltransferase (γ-GT) and aspartate aminotransferase (AST) are common biomarkers for evaluating liver function, and we hypothesized that the γ-GT/AST ratio in combination with PIVKA-II and AFP would improve the diagnosis of early-stage HBV-related HCC. AIM To evaluate the diagnostic value of γ-GT/AST ratio alone or in combination with PIVKA-II and AFP in HBV-related HCC. METHODS Serum levels of γ-GT, AST, PIVKA-II, and AFP were detected and analysed in 176 patients with HBV-related HCC and in 359 patients with chronic hepatitis B. According to tumour size and serum level of HBV DNA, HBV-related HCC patients were divided into the following categories: Early-stage HCC patients, HCC patients, HBV DNA positive (HBV DNA+) HCC patients, and HBV DNA negative (HBV DNA-) HCC patients. Receiver-operating characteristic (ROC) curves were used to analyse and compare the diagnostic value of the single and combined detection of various biomarkers in different types of HBV-related HCC. RESULTS Tumour size was positively correlated with serum levels of PIVKA-II and AFP in HCC patients (r = 0.529, aP < 0.001 and r = 0.270, bP < 0.001, respectively), but there was no correlation between tumour size and the γ-GT/AST ratio (r = 0.073, P = 0.336). The areas under the receiver-operating characteristic curves (AUROCs) of the γ-GT/AST ratio in early-stage HCC patients, HBV DNA+ HCC patients and HBV DNA- HCC patients were not significantly different from that in the total HCC patients (0.754, 0.802, and 0.705 vs 0.779, respectively;P > 0.05). When PIVKA-II was combined with the γ-GT/AST ratio in the diagnosis of earlystage HCC, HCC, and HBV DNA+ HCC, the AUROCs of PIVKA-II increased, with values of 0.857 vs 0.835, 0.925 vs 0.913, and 0.958 vs 0.954, respectively. When AFP was combined with the γ-GT/AST ratio in the diagnosis of early-stage HCC, HCC, HBV DNA+ HCC, and HBV DNA- HCC, the AUROCs of AFP increased, with values of 0.757 vs 0.621, 0.837 vs 0.744, 0.868 vs 0.757, and 0.840 vs 0.828, respectively. CONCLUSION The γ-GT/AST ratio may be better than PIVKA-II and AFP in the diagnosis of early-stage HBV-related HCC, and its combination with PIVKA-II and AFP can improve the diagnostic value for HBV-related HCC.

Subclinical atherosclerosis is linked to small intestinal bacterial overgrowth via vitamin K2-dependent mechanisms

AIM To assess the rate of matrix Gla-protein carboxylation in patients with small intestinal bacterial overgrowth(SIBO) and to decipher its association with subclinical atherosclerosis.METHODS Patients with suspected SIBO who presented with a low risk for cardiovascular disease and showed no evidence of atherosclerotic plaques were included in the study. A glucose breath test was performed in order to confirm the diagnosis of SIBO and vascular assessment was carried out by ultrasound examination. Plasma levels of the inactive form of MGP(dephosphorylateduncarboxylated matrix Gla-protein) were quantified by ELISA and vitamin K2 intake was estimated using a food frequency questionnaire.RESULTS Thirty-nine patients were included in the study. SIBO was confirmed in 12/39(30.8%) patients who also presented with a higher concentration ofdephosphorylated-uncarboxylated matrix Gla-protein(9.5 μg/L vs 4.2 μg/L; P = 0.004). Arterial stiffness was elevated in the SIBO group(pulse-wave velocity 10.25 m/s vs 7.68 m/s; P = 0.002) and this phenomenon was observed to correlate linearly with the levels of dephosphorylated-uncarboxylated matrix Gla-protein(β = 0.220, R2 = 0.366, P = 0.03). Carotid intima-media thickness and arterial calcifications were not observed to be significantly elevated as compared to controls.CONCLUSION SIBO is associated with reduced matrix Gla-protein activation as well as arterial stiffening. Both these observations are regarded as important indicators of subclinical atherosclerosis. Hence, screening for SIBO, intestinal decontamination and supplementation with vitamin K2 has the potential to be incorporated into clinical practice as additional preventive measures.

Protein induced by vitamin K absence or antagonist Ⅱ-producing gastric cancer

Protein induced by vitamin K absence or antagonist Ⅱ(PIVKA-Ⅱ) is a putative specific marker of hepatocellular carcinoma(HCC),but it may also be produced by asmall number of gastric cancers.To date,16 cases of PIVKA-Ⅱ-producing gastric cancer have been reported,2 of which were reported by us and all of which were identified in Japan.There are no symptoms specific to PIVKA-Ⅱ-producing gastric cancer,and the representative clinical symptoms are general fatigue,appetite loss,and upper abdominal pain.Serum alpha-feto-protein(AFP)levels are also increased in almost allcases.Liver metastasis is observed in approximately 80% of cases and portal vein tumor thrombus is ob-served in approximately 20% of cases.Differential diagnosis between metastatic liver tumor and HCC is often difficult.Grossly,almost all cases appear as advanced gastric cancer.Histologically,a hepatoid pattern is observed in many cases,in addition to a moderately to poorly differentiated adenocarcinoma component.The production of PIVKA-Ⅱ and AFP is usually confirmed using immunohistochemical staining.Treatment and prognosis largely depends on the existence of liver meta-stasis,and the prognosis of patients with liver metas-tasis is very poor.PIVKA-Ⅱ may be produced during the hepatocellular metaplasia of the tumor cells.

Vitamin K and hepatocellular carcinoma: The basic and clinic

Vitamin K(VK), which was originally identified as a cofactor involved in the production of functional coagulation factors in the liver, has been shown to be involved in various aspects of physiological and pathological events, including bone metabolism, cardiovascular diseases and tumor biology. The mechanisms and roles of VK are gradually becoming clear. Several novel enzymes involved in the VK cycle were identified and have been shown to be linked to tumorigenesis. The VKs have been shown to suppress liver cancer cell growth through multiple signaling pathways via the transcription factors and protein kinases. A VK2 analog was applied to the chemoprevention of hepatocellular carcinoma(HCC) recurrence after curative therapy and was shown to have beneficial effects, both in the suppression of HCC recurrence and in patient survival. Although a large scale randomized control study failed to demonstrate the suppression of HCC recurrence, a meta-analysis suggested a beneficial effect on the long-term survival of HCC patients. However, the beneficial effects of VK administration alone were not sufficient to prevent or treat HCC in clinical settings. Thus its combination with other anti-cancer reagents and the development of more potent novel VK derivatives are the focus of ongoing research which seeks to achieve satisfactory therapeutic effects against HCC.

Regression of hepatocellular carcinoma during vitamin K administration

An 85-year-old man with HCV infection and diabetes mellitus was diagnosed as having hepatocellular carcinoma (HCC, 13 cm in diameter) based on high serum alpha-fetoprotein (AFP),AFP-L3,and des-γ-carboxy prothrombin levels as well as typical enhancement pattern on contrast-enhanced CT. The patient did not receive any interventional treatments because of advanced age and the advanced stage of HCC.He chose to take vitamin K,which was reported to suppress the growth of HCC in vitro. Three months after starting vitamin K, all three tumor markers were normalized and HCC was markedly regressed, showing no enhancement in the early arterial phase on CT. Here we present the report describing the regression of HCC during the administration of vitamin K.