Antenatal steroid as an independent risk factor for vitamin K2 deficiency in newborns: A Chinese single-center, retrospective study.

OBJECTIVES: To identified vitamin K2 deficiency rate and risk factors among newborns in China and assess the importance of high-risk maternal intakes of vitamin K2. METHODS: This retrospective study was performed at the Neonatology Department, the Affiliated Hospital of Guangdong Medical University, China. Routinely collected mother-neonate hospitalization data from July 2020 to January 2021 were analyzed. In total, data from 200 neonates who had completed vitamin K2 tests were utilized to assess the prevalence of vitamin K2 deficiency and identify the potential risk factors. According to the vitamin K2 level, the neonates were divided into 2 groups: cases (vitamin K2 deficiency) and controls (no vitamin K2 deficiency). The potential risk factors for vitamin K2 deficiency were evaluated by univariate and multivariate logistic regression. RESULTS: The vitamin K2 level in 24 of the 200 neonates was undetectable (<0.05 ng/mL). The prevalence of low serum vitamin K2 (<0.1 ng/ml) was 33%. Study subjects with antenatal corticosteroids use had an approximately 5-fold greater risk of developing vitamin K2 deficiency. In the univariate analyses, small-for-gestational-age (SGA), caesarean section, maternal gestational diabetes and premature rupture of the membranes were risk factors for vitamin K2 deficiency. In the multivariate logistic regression analysis, high antenatal corticosteroids use, cesarean section, and SGA were independently associated with vitamin K2 deficiency. CONCLUSION: The present study demonstrated that antenatal corticosteroids use is independently associated with vitamin K2 deficiency. This finding highlights the importance of routine vitamin K2 supplementation in late-stage pregnant women and neonates in China.

Exclusively breastmilk-fed preterm infants are at high risk of developing subclinical vitamin K deficiency despite intramuscular prophylaxis at birth.

BACKGROUND: There is near-global consensus that all newborns be given parenteral vitamin K1 (VK1 ) at birth as prophylaxis against VK deficiency bleeding (VKDB). Breastmilk has a low VK content and cases of late VKDB are reported in exclusively breastmilk-fed preterm infants despite VK prophylaxis at birth. OBJECTIVES: To assess the prevalence of functional VK insufficiency in preterm infants based on elevated under-γ-carboxylated (Glu) species of Gla proteins, factor II (PIVKA-II), and osteocalcin (GluOC), synthesized by liver and bone, respectively. PATIENTS/METHODS: Prospective, multicenter, observational study in preterm infants born <33 weeks' gestation. Blood samples and dietary history were collected before hospital discharge, and after discharge at 2-3 months' corrected age. Outcome measures were serum VK1 , PIVKA-II, and %GluOC (GluOC as a percentage of the sum of GluOC plus GlaOC) compared between exclusively breastmilk-fed and formula/mixed-fed infants after discharge. RESULTS: After discharge, breastmilk-fed babies had significantly lower serum VK1 (0.15 vs. 1.81 µg/L), higher PIVKA-II (0.10 vs. 0.02 AU/ml) and higher %GluOC (63.6% vs. 8.1%) than those receiving a formula/mixed-feed diet. Pre-discharge (based on elevated PIVKA-II), only one (2%) of 45 breastmilk-fed infants was VK insufficient. After discharge, eight (67%) of 12 exclusively breastmilk-fed babies were VK insufficient versus only one (4%) of 25 formula/mixed-fed babies. CONCLUSIONS: Preterm infants who remain exclusively or predominantly human breastmilk-fed after neonatal unit discharge are at high risk of developing subclinical VK deficiency in early infancy. Routine postdischarge VK1 supplementation of breastfed infants to provide intakes comparable to those from formula milks should prevent this deficiency.

Vitamin K Supplementation in Chronic Kidney Disease Patients: Where is the Evidence?

Vascular calcification (VC) is highly prevalent in Chronic Kidney Disease (CKD) patients, progresses gradually with deterioration of kidney function and is a strong, independent predictor of cardiovascular (CV) mortality. Matrix Gla Protein (MGP), the most potent inhibitor of VC, requires vitamin K as a co-factor to become biologically active. Accumulating epidemiological data have associated vitamin K depletion with VC progression and CV outcomes. CKD patients are characterized by poor vitamin K status and at the same time, pronounced CV calcification. In early and advanced CKD, including end-stage kidney disease, exogenous supplementation of vitamin K (especially with menaquinone 7, its most bioavailable form) might decrease the inactive form of MGP (dephosphorylated, uncarboxylated MGP) and probably retard the progression or even reverse VC. Here, we focus and discuss the interventional human studies of vitamin K supplementation in CKD patients and suggest future directions in this area of interest.

Vitamin K and cardiovascular complications in chronic kidney disease patients.

Vitamin K, well known for its role in coagulation, encompasses 2 major subgroups: vitamin K1 is exclusively synthesized by plants, whereas vitamin K2 mostly originates from bacterial synthesis. Vitamin K serves as a cofactor for the enzyme γ-glutamyl carboxylase, which carboxylates and thereby activates various vitamin K-dependent proteins. Several vitamin K-dependent proteins are synthesized in bone, but the role of vitamin K for bone health in chronic kidney disease patients, in particular the prevention of osteoporosis, is still not firmly established. Herein, we focus on another prominent action of vitamin K, in particular vitamin K2 (namely, the activation of matrix γ-carboxyglutamic acid protein, the most potent inhibitor of cardiovascular calcifications). Multiple observational studies link relative vitamin K deficiency or low intake to cardiovascular calcification progress, morbidity, and mortality. Patients with advanced chronic kidney disease are particularly vitamin K deficient, in part because of dietary restrictions but possibly also due to impaired endogenous recycling of vitamin K. At the same time, this population is characterized by markedly accelerated cardiovascular calcifications and mortality. High-dose dietary supplementation with vitamin K2, in particular the most potent form, menaquinone 7, can potently reduce circulating levels of dephosphorylated uncarboxylated (i.e., inactive matrix γ-carboxyglutamic acid protein) in patients with end-stage kidney disease. However, despite this compelling data basis, several randomized controlled trials with high-dose menaquinone 7 supplements in patients with advanced chronic kidney disease have failed to confirm cardiovascular benefits. Herein, we discuss potential reasons and solutions for this.

Vitamin K and vascular calcification.

PURPOSE OF REVIEW: Vascular calcification is a common and important cardiovascular risk factor in patients with chronic kidney disease (CKD). Recent advances in the understanding of the biology of vascular calcification implicate vitamin K-dependent proteins as important regulators in this process. This review highlights recent key advances in vascular biology, epidemiology, and clinical trials in this rapidly evolving field. RECENT FINDINGS: Vitamin K deficiency is associated with increasing severity of vascular calcification among patients with CKD, but the relationship with cardiovascular disease and mortality is inconsistent. Vitamin K may reduce calcification propensity by improving the activity of vitamin K-dependent calcification inhibitors or by down-regulating components of the innate immune system to reduce inflammation. However, recent randomized controlled trials in patients with diabetes, CKD, renal transplant, and on hemodialysis have failed to demonstrate improvement in vascular calcification or stiffness after vitamin K treatment. SUMMARY: Current evidence does not support a clinically useful role for vitamin K supplementation to prevent or reverse vascular calcification in patients with CKD. Knowledge gaps remain, particularly whether higher doses of vitamin K, longer duration of supplementations, or use a vitamin K as a part of a package of measures to counteract vascular calcification might be effective.

Vitamin K for the Treatment of Cardiovascular Disease in End-Stage Renal Disease Patients: Is there Hope?

In Chronic Kidney Disease, vascular calcification (VC) is highly prevalent even at early stages and is gradually enhanced, along with disease progression to End-Stage Renal Disease (ESRD). The calcification pattern in uremia includes all types of mineralization and contributes to the heavy cardiovascular (CV) burden that is common in these patients. Ectopic mineralization is the result of the imbalance between inhibitors and promoters of vascular calcification, with the latter overwhelming the former. The most powerful, natural inhibitor of calcification is Matrix Gla Protein (MGP), a small vitamin K dependent protein, secreted by chondrocytes and vascular smooth muscle cells. In uremia, MGP was reported as the only molecule able to reverse VC by "sweeping" calcium and hydroxyapatite crystals away from the arterial wall. To become biologically active, this protein needs to undergo carboxylation and phosphorylation, reactions highly dependent on vitamin K status. The inactive form of MGP reflects the deficiency of vitamin K and has been associated with CV events and mortality in ESRD patients. During the past decade, vitamin K status has emerged as a novel risk factor for vascular calcification and CV disease in various populations, including dialysis patients. This review presents evidence regarding the association between vitamin K and CV disease in ESRD patients, which are prone to atherosclerosis and atheromatosis.

Vitamins K and D deficiency in severe motor and intellectually disabled patients.

OBJECTIVES: We aimed to determine serum 25-hydroxyvitamin D (25(OH)D) and undercarboxylated osteocalcin (ucOC) levels in severe motor and intellectual disabilities (SMID) patients and their association with bone turnover biomarkers. METHODS: We assessed vitamin D and K levels as indicators of osteoporosis in institutionalized adults with SMID. From December 2019 to February 2020, 93 institutionalized patients (48 men, 45 women; median age, 49 years) underwent annual routine examinations. Serum ucOC, 25(OH)D, bone-specific alkaline phosphatase (BAP), and tartrate-resistant acid phosphatase A 5b (TRACP-5b) levels as bone formation and resorption markers and calcium and phosphorous levels were measured. Vitamin K deficiency was indirectly assessed based on ucOC levels. RESULTS: Mean ucOC levels were higher than normal (i.e., vitamin K deficiency). Serum 25(OH)D levels were markedly diminished. Overall, 86% of patients had deficient 25(OH)D levels. These 25(OH)D-deficient patients had higher ucOC levels. Multiple linear regression analysis revealed an inverse correlation between 25(OH)D and ucOC levels. ucOC levels were significantly higher and 25(OH)D levels were significantly lower in tube feeding. TRACP-5b levels were significantly higher in elderly than in young women. BAP and TRACP-5b levels were normal in adults. No relationship existed between vitamin D and antiepileptic drug use. CONCLUSIONS: Vitamin K and D co-deficiency was common in SMID patients. Vitamin K and D deficiencies were worse in tube-fed patients than in oral intake patients. SMID patients should undergo regular monitoring of vitamin D and K levels and supplementation of these vitamins.

Vitamin K deficiency: an emerging player in the pathogenesis of vascular calcification and an iatrogenic consequence of therapies in advanced renal disease.

Vascular calcification is a known complication of chronic kidney disease (CKD). The prevalence of vascular calcification in patients with non-dialysis-dependent CKD stages 3-5 has been shown to be as high as 79% (20). Vascular calcification has been associated with increased risk for mortality, hospital admissions, and cardiovascular disease (6, 20, 50, 55). Alterations in mineral and bone metabolism play a pivotal role in the pathogenesis of vascular calcification in CKD. As CKD progresses, levels of fibroblast growth factor-23, parathyroid hormone, and serum phosphorus increase and levels of 1,25-(OH)2 vitamin D decrease. These imbalances have been linked to the development of vascular calcification. More recently, additional factors have been found to play a role in vascular calcification. Matrix G1a protein (MGP) in its carboxylated form (cMGP) is a potent inhibitor of vascular calcification. Importantly, carboxylation of MGP is dependent on the cofactor vitamin K. In patients with CKD, vitamin K deficiency is prevalent and is exacerbated by warfarin, which is frequently used for anticoagulation. Insufficient bioavailability of vitamin K reduces the amount of cMGP available, and, therefore, it may lead to increased risk of vascular calcification. In vitro studies have shown that in the setting of a high-phosphate environment and vitamin K antagonism, human aortic valve interstitial cells become calcified. In this article, we discuss the pathophysiological consequence of vitamin K deficiency in the setting of altered mineral and bone metabolism, its prevalence, and clinical implications in patients with CKD.

Temporal association between serious bleeding and immunization: vitamin K deficiency as main causative factor.

BACKGROUND: Bleeding as an adverse event following immunization (AEFI) that is rarely reported in children, although it can be a parental concern. Bleeding episodes ranging in severity from mild to severe and defined as any external and/or internal bleeding can be caused by acquired or hereditary disorders. This study analyzes whether bleeding episodes in children that were recorded as AEFIs are causally associated with immunization and elaborates their etiology. METHODS: A cross-sectional study of 388 AEFI cases in children from West Java Provincial Committee in Indonesia confirmed by case findings from 2000 until 2017. RESULTS: Of the total number of cases studied, 55 (14%) involved children aged 5 days to 12 years who presented with bleeding and were referred to a provincial hospital. Analysis revealed that 32 cases were most likely caused by acquired prothrombin complex deficiency (APCD) and 30 of these APCD cases were strongly suspected to be manifestations of vitamin K deficiency bleeding (VKDB). All VKDB subjects were aged 5 days to 3 months without a history of administration of prophylactic vitamin K. When a World Health Organization classification was used, most bleeding cases in this study became coincidental events with a temporal association with immunization. A causality assessment suggested that these cases were causally unrelated. CONCLUSION: Most cases of bleeding reported as an AEFI were found to be VKDB, which is considered a coincidental event following immunization with a temporal association, and an unrelated category based on the results of a causality assessment. Vitamin K should be administered to all newborns as a prophylactic and AEFI surveillance should be improved based on the low numbers of AEFI reported in Indonesia.

Prevalence of vitamin K deficiency in older people with hip fracture.

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.

Diversity of Gut Microbiota Affecting Serum Level of Undercarboxylated Osteocalcin in Patients with Crohn's Disease.

Several reports have indicated a possible link between decreasing plasma levels of vitamin K and bone mineral density. It has been suggested that intestinal bacteria contribute to maintenance of vitamin K. Several factors are involved in the reduction of vitamin K in patients with Crohn's disease (CD). We aimed to assess the relationship between gut microbiota and alternative indicators of vitamin K deficiency in patients with CD. We collected the feces of 26 patients with clinically inactive CD. We extracted 16S rRNA from the intestinal bacteria in the feces and amplified it by polymerase chain reaction. The generated polymerase chain reaction product was analyzed using a 16S metagenomic approach by Illumina Miseq platform. Serum undercarboxylated osteocalcin concentration was used as an alternative indicator of vitamin K deficiency. There was a significant negative correlation between serum undercarboxylated osteocalcin and mean Chao1 index in cases of low activity. The diversity of the gut microbiota was significantly lower, and Ruminococcaceae and Lachnospiraceae were significantly decreased in the vitamin K-deficient group in comparison to the vitamin K-normal group. Taken together, these data suggested the significance of investigating the gut microbiota even in patients with clinically inactive CD for improving patients' vitamin K status.

Prophylactic Vitamin K Administration in Neonates on Prolonged Antibiotic Therapy: A Randomized Controlled Trial.

OBJECTIVE: To compare the prevalence of vitamin K deficiency after intramuscular vitamin K or no treatment in neonates with sepsis on prolonged (>7 days) antibiotic therapy. STUDY DESIGN: Open label randomized controlled trial. SETTING: Level 3 Neonatal Intensive Care Unit (NICU). PARTICIPANTS: Neonates with first episode of sepsis on antibiotics for ≥7 days were included. Neonates with clinical bleeding, vitamin K prior to start of antibiotic therapy (except the birth dose), cholestasis or prenatally diagnosed bleeding disorder were excluded. INTERVENTIONS: Randomized to receive 1 mg vitamin K (n=41) or no vitamin K (n=39) on the 7th day of antibiotic therapy. MAIN OUTCOME MEASURES: Vitamin K deficiency defined as Protein Induced by Vitamin K Absence (PIVKA-II) >>2 ng/mL after 7 ± 2 days of enrolment. RESULTS: The prevalence of vitamin K deficiency was 100% (n=80) at enrolment and it remained 100% even after 7 ± 2 days of enrolment in both the groups. CONCLUSIONS: Neonates receiving prolonged antibiotics have universal biochemical vitamin K deficiency despite vitamin K administration on 7th day of antibiotic therapy.

Multiple vitamin deficiencies additively increase the risk of incident fractures in Japanese postmenopausal women.

The associations of multiple vitamin deficiencies on incident fractures were uncertain, the relationships between serum vitamin markers and incident bone fractures were investigated in Japanese postmenopausal women. The number of deficiencies was additively associated with incident fracture after adjustment for possible confounding factors including the treatment of osteoporosis. INTRODUCTION: To evaluate the associations of multiple vitamin deficiencies on incident fractures, the relationships between serum vitamin markers and incident bone fractures were investigated in Japanese postmenopausal women. METHODS: This analysis used a subset of the ongoing cohort maintained by a primary care institution. Inclusion criteria of the present study were postmenopausal women aged ≥ 50 years, without vitamin supplementation and secondary osteoporosis. Baseline serum concentrations of 25-hydroxyvitamin D (25(OH)D), undercarboxylated osteocalcin (ucOC), and homocysteine (Hcy) were measured to assess vitamin D, vitamin K, and vitamin B, respectively. Since 25(OH) D positively relates to vitamin D, ucOC and Hcy negatively relate to vitamin K and vitamin B nutrients, respectively, the subjects with lower (25(OH)D) or higher (ucOC or Hcy) values than each median value was defined as subjects with the corresponding vitamin deficiency. Subjects were divided into four groups according to the number of deficiency: no deficiency, single deficiency, double deficiencies, and triple deficiencies. Relationships between the vitamin deficiencies and incident fractures were evaluated by Cox regression analysis. RESULTS: A total of 889 subjects were included in this analysis; their mean and SD age was 68.3 ± 9.5 years, and the follow-up period was 6.3 ± 5.1 years. The numbers of subjects in the four groups were 139 (15.6%), 304 (34.2%), 316 (35.5%), and 130 (14.6%) for the groups with no, single, double, and triple deficiencies, respectively. Incident fractures were observed in 264 subjects (29.7%) during the observation period. The number of deficiencies was significantly associated with incident fracture (hazard ratio 1.25, 95% confidence interval 1.04-1.50, P = 0.018) after adjustment for possible confounding factors including the treatment of osteoporosis. CONCLUSION: Accumulation of vitamin deficiencies was related to incident fractures.

Clinical and pathological features of combined hepatocellular-cholangiocarcinoma compared with other liver cancers.

BACKGROUND AND AIM: Combined hepatocellular-cholangiocarcinoma (CHC) is a primary liver cancer containing both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) elements. Its reported clinicopathological features and prognoses have varied because of its low prevalence. This study aimed to clarify these aspects of CHC. METHODS: We enrolled 28 patients with CHC, 1050 with HCC, and 100 with ICC and compared the clinicopathological characteristics and prognosis of CHC with HCC and ICC. We also analyzed prognostic factors, recurrence patterns, and management in CHC patients. RESULTS: The incidences of hepatitis B virus and high α-fetoprotein and protein induced by vitamin K absence or antagonists-II levels were significantly higher among CHC compared with ICC patients. Multiple tumors were more frequent in CHC compared with the other groups, while vascular invasion and lymph node metastasis were more frequent in the CHC than the HCC group. The 5-year overall survival and disease-free survival rates for CHC were 25.1% and 22.6%, respectively. Overall survival was significantly lower than for HCC (P < 0.001) but not ICC (P = 0.152), while disease-free survival was significantly lower than for HCC and ICC (P = 0.008 and P = 0.005, respectively). Multivariate analysis identified carcinoembryonic antigen levels and tumor size as independent predictors in patients with CHC. CONCLUSIONS: The clinical features of CHC, including sex, hepatitis B virus infection, α-fetoprotein, and protein induced by vitamin K absence or antagonists-II levels, were similar to HCC, while its prognosis and pathological features, including vascular invasion and lymph node metastasis, were similar to ICC. Carcinoembryonic antigen levels and tumor size were independent prognostic factors in patients with CHC.

Vitamins D and K as Factors Associated with Osteopathy in Chronic Pancreatitis: A Prospective Multicentre Study (P-BONE Study).

BACKGROUND: Osteopathy is common in patients with chronic pancreatitis (CP), but previous studies carry several limitations. Vitamin K is essential for bone metabolism, but its role in this setting has never been investigated. Our aim is to assess the prevalence of osteoporosis and osteopenia in CP patients, and to investigate the association between osteopathy and CP features and nutritional parameters, especially vitamin D and K levels. METHODS: Multicentre cross-sectional study on CP patients diagnosed according to M-ANNHEIM criteria. Bone density was evaluated by dual-energy X-ray absorptiometry and pancreatic function by faecal elastase. Nutritional evaluation included vitamin D and vitamin K. Differences between patients with or without osteopathy were evaluated. The association between investigated variables and bone density were analysed with logistic regression analysis. RESULTS: In total, 211 CP patients were enrolled at eight Centres (67% men; mean age 60). In total, 18% had advanced-marked CP, 56% suffered from pancreatic exocrine insufficiency and disease aetiology was alcoholic in 43%. Vitamin D and K were deficient in 56% and 32%, respectively. Osteopenia was diagnosed in 42% and osteoporosis in 22%. In the multivariate analysis, female sex (OR 2.78), age (OR 1.07 per year) and higher BMI (OR 0.84) were associated with the presence of osteoporosis. In male patients, the only factor associated with osteoporosis was vitamin K deficiency (OR 4.23). CONCLUSION: The present data confirm a high rate of osteopathy in CP patients and highlight the relevance of vitamin K deficiency as only factor associated with osteoporosis in male patients for the first time.

The Vitamin K Metabolome in Chronic Kidney Disease.

The purpose of this review is to summarize the research to date on the impact of chronic kidney disease (CKD) on the vitamin K metabolome. Vitamin K-dependent proteins contribute to cardiovascular disease (CVD) prevention via the prevention of ectopic mineralization. Sub-clinical vitamin K deficiency is common in CKD patients, and evidence suggests that it may contribute to the CVD burden in this population. Research from animal models suggests that CKD alters tissue measures of the two predominant forms of vitamin K: KI and MK-4. The expression and/or activity of enzymes that regulate the recycling of vitamin K and the carboxylation of vitamin K-dependent proteins also appear to be altered in CKD. Evidence suggests that statins, a common pharmaceutical prescribed to CKD patients to prevent cardiovascular events, may impact the metabolism of vitamin K and therefore contribute to its relative inefficiency at preventing CVD in this population as kidney disease progresses. Human research on the tissue vitamin K metabolome in CKD patients is lacking.

Prevalencia de deficiencia de vitamina K y factores asociados en pacientes con fibrosis quística sin aporte suplementario / Prevalence of vitamin K deficiency and associated factors in non-supplemented cystic fibrosis patients

Introducción. La deficiencia de vitamina K es prevalente en pacientes con fibrosis quística (FQ) aun con aporte suplementario. Se desconocen factores de riesgo fiables para determinar su ocurrencia. Nuestro objetivo fue evaluar la prevalencia de deficiencia de vitamina K y factores asociados en los pacientes con FQ que no recibían aporte suplementario. Métodos. Se determinaron protrombina inducida por ausencia de vitamina K (PIVKA-II) y osteocalcina infracarboxilada (OCic). Se evaluó el estado clínico y su relación con la deficiencia de vitamina K. El análisis estadístico incluyó prueba de Mann-Whitney, ANOVA o Kruskal-Wallis, prueba χ² o prueba de Fisher-Freeman-Halton y regresión logística múltiple lineal y escalonada hacia adelante. Resultados. Se incluyeron 79 pacientes con FQ de entre 0,4-25,3 años. Se observaron valores anómalos de PIVKA-II y OCic en 56 (70,9%) y 45 (57,0%) pacientes. Los pacientes con PIVKA-II elevada eran significativamente mayores (p = 0,0184) y tenían puntajes Z de peso corporal (p= 0,0297) inferiores a los pacientes que tenían concentraciones normales. No se hallaron diferencias entre los pacientes con OCic normal o patológica. Se notificaron valores anómalos de PIVKA-II y OCic más frecuentemente en pacientes con dos mutaciones graves en el gen CFTR y con un estado nutricional malo/deficiente. Los análisis de regresión múltiple lineal y de regresión múltiple escalonada hacia adelante no revelaron factores predictivos sólidos para determinar la deficiencia de vitamina K. Conclusión. La deficiencia de vitamina K es altamente prevalente durante la evolución natural de la fibrosis quística. No se hallaron determinantes clínicos fiables para precisar su ocurrencia.

Introduction. Vitamin K deficiency is highly prevalent in cystic fibrosis (CF) patients despite supplementation. Moreover, no reliable risk factors for its occurrence are known. The aim was to assess the prevalence of vitamin K deficiency and associated factors in non-supplemented CF patients. Methods. Prothrombin concentration induced by vitamin K absence (PIVKA-II) and the undercarboxylated osteocalcin percentage (u-OC) were determined. In all patients clinical status was assessed and its relation to vitamin K deficiency determined. The following tests were used for statistical analysis: Mann-Whitney test, ANOVA test or the Kruskal Wallis test, the chi-squared test or the Fisher-Freeman-Halton test, and multiple linear and multiple forward stepwise logistic regression analysis. Results. The study group comprised 79 CF patients aged 0.4-25.3 years. PIVKA-II and u-OC were abnormal in 56 (70.9%) and 45 (57.0%) patients. Patients with elevated PIVKA-II were significantly older (p= 0.0184) and had lower Z-score values for body weight (p= 0.0297) than those with normal concentrations. Patients with normal or pathological u-OC percentage did not differ. Abnormal PIVKA-II and u-OC were reported more frequently in subjects with two severe CFTR mutations and with worse/poor nutritional status. Multiple linear and forward stepwise regression analyses did not reveal strong predictive factors of vitamin K deficiency. Conclusion. Vitamin K deficiency is highly prevalent in the natural course of cystic fibrosis. There are no reliable clinical determinants of its occurrence.

Prevalence of vitamin K deficiency and associated factors in non-supplemented cystic fibrosis patients. / Prevalencia de deficiencia de vitamina K y factores asociados en pacientes con fibrosis quística sin aporte suplementario.

INTRODUCTION: Vitamin K deficiency is highly prevalent in cystic fibrosis (CF) patients despite supplementation. Moreover, no reliable risk factors for its occurrence are known. The aim was to assess the prevalence of vitamin K deficiency and associated factors in non-supplemented CF patients. METHODS: Prothrombin concentration induced by vitamin K absence (PIVKA-II) and the undercarboxylated osteocalcin percentage (u-OC) were determined. In all patients clinical status was assessed and its relation to vitamin K deficiency determined. The following tests were used for statistical analysis: Mann-Whitney test, ANOVA test or the Kruskal Wallis test, the chi-squared test or the Fisher-Freeman-Halton test, and multiple linear and multiple forward stepwise logistic regression analysis. RESULTS: The study group comprised 79 CF patients aged 0.4-25.3 years. PIVKA-II and u-OC were abnormal in 56 (70.9%) and 45 (57.0%) patients. Patients with elevated PIVKA-II were significantly older (p= 0.0184) and had lower Z-score values for body weight (p= 0.0297) than those with normal concentrations. Patients with normal or pathological u-OC percentage did not differ. Abnormal PIVKA-II and u-OC were reported more frequently in subjects with two severe CFTR mutations and with worse/poor nutritional status. Multiple linear and forward stepwise regression analyses did not reveal strong predictive factors of vitamin K deficiency. CONCLUSION: Vitamin K deficiency is highly prevalent in the natural course of cystic fibrosis. There are no reliable clinical determinants of its occurrence.

INTRODUCCIÓN: La deficiencia de vitamina K es prevalente en pacientes con fibrosis quística (FQ) aun con aporte suplementario. Se desconocen factores de riesgo fiables para determinar su ocurrencia. Nuestro objetivo fue evaluar la prevalencia de deficiencia de vitamina K y factores asociados en los pacientes con FQ que no recibían aporte suplementario. MÉTODOS: Se determinaron protrombina inducida por ausencia de vitamina K (PIVKA-II) y osteocalcina infracarboxilada (OCic). Se evaluó el estado clínico y su relación con la deficiencia de vitamina K. El análisis estadístico incluyó prueba de Mann-Whitney, ANOVA o Kruskal-Wallis, prueba χ2 o prueba de Fisher-Freeman-Halton y regresión logística múltiple lineal y escalonada hacia adelante. RESULTADOS: Se incluyeron 79 pacientes con FQ de entre 0,4-25,3 años. Se observaron valores anómalos de PIVKA-II y OCic en 56 (70,9%) y 45 (57,0%) pacientes. Los pacientes con PIVKA-II elevada eran significativamente mayores (p = 0,0184) y tenían puntajes Z de peso corporal (p= 0,0297) inferiores a los pacientes que tenían concentraciones normales. No se hallaron diferencias entre los pacientes con OCic normal o patológica. Se notificaron valores anómalos de PIVKA-II y OCic más frecuentemente en pacientes con dos mutaciones graves en el gen CFTR y con un estado nutricional malo/deficiente. Los análisis de regresión múltiple lineal y de regresión múltiple escalonada hacia adelante no revelaron factores predictivos sólidos para determinar la deficiencia de vitamina K. CONCLUSIÓN: La deficiencia de vitamina K es altamente prevalente durante la evolución natural de la fibrosis quística. No se hallaron determinantes clínicos fiables para precisar su ocurrencia.

Coagulopathy in Zellweger spectrum disorders: a role for vitamin K.

INTRODUCTION: Zellweger spectrum disorders (ZSDs) are caused by an impairment of peroxisome biogenesis, resulting in multiple metabolic abnormalities. This leads to a range of symptoms, including hepatic dysfunction and coagulopathy. This study evaluated the incidence and severity of coagulopathy and the effect of vitamin K supplementation orally and IV in ZSD. METHODS: Data were retrospectively retrieved from the medical records of 30 ZSD patients to study coagulopathy and the effect of vitamin K orally on proteins induced by vitamin K absence (PIVKA-II) levels. Five patients from the cohort with a prolonged prothrombin time, low factor VII, and elevated PIVKA-II levels received 10 mg of vitamin K IV. Laboratory results, including thrombin generation, at baseline and 72 h after vitamin K administration were examined. RESULTS: In the retrospective cohort, four patients (13.3%) experienced intracranial bleedings and 14 (46.7%) reported minor bleeding. No thrombotic events occurred. PIVKA-II levels decreased 38% after start of vitamin K therapy orally. In the five patients with a coagulopathy, despite treatment with oral administration of vitamin K, vitamin K IV caused an additional decrease (23%) of PIVKA-II levels and increased thrombin generation. CONCLUSION: Bleeding complications frequently occur in ZSD patients due to liver disease and vitamin K deficiency. Vitamin K deficiency is partly corrected by vitamin K supplementation orally, and vitamin K administered IV additionally improves vitamin K status, as shown by further decrease of PIVKA-II and improved thrombin generation.