RESUMO
Background: There are few studies investigating the relationship between serum vitamin B6 and mortality risk in the elderly. This study hereby evaluated the associations between biomarkers of serum vitamin B6 status and cardiovascular, cancer, and all-cause mortality risks in the elderly. Methods: Our study included a total of 4,881 participants aged 60 years or older from the National Health and Nutrition Examination Survey (NHANES) 2005-2010. Serum vitamin B6 status was estimated based on levels of pyridoxal 5'-phosphate (PLP), 4-pyridoxic acid (4-PA), and vitamin B6 turnover rate (4-PA/PLP) detected by high-performance liquid chromatography. Survival status and corresponding causes of death were matched through the National Death Index records through December 31, 2019. Multivariate Cox regression model was adopted to assess the relationships between serum vitamin B6 status and the risk of mortality. Results: During a median follow-up period of 10.33 years, 507 cardiovascular deaths, 426 cancer deaths, and 1995 all-cause deaths were recorded, respectively. In the multivariate-adjusted Cox model, the hazard ratios (HRs) and 95% confidence intervals (CIs) for the highest versus the lowest quartiles of PLP, 4-PA, and 4-PA/PLP were 0.70(0.54-0.90), 1.33(0.88-2.02), and 2.01(1.41-2.79) for cardiovascular mortality, 0.73(0.52-1.02), 1.05(0.71-1.57), and 1.95(1.25-3.05) for cancer mortality, and 0.62(0.53-0.74), 1.05(0.82-1.34), and 2.29(1.87-2.79) for all-cause mortality, respectively. Conclusion: Our study found that lower serum PLP levels were associated with increased risks of cardiovascular and all-cause mortality among the elderly population. And higher vitamin B6 turnover rate was associated with increased risks of cardiovascular, cancer, and all-cause mortality.
Assuntos
Doenças Cardiovasculares , Neoplasias , Vitamina B 6 , Humanos , Feminino , Neoplasias/mortalidade , Neoplasias/sangue , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/sangue , Masculino , Idoso , Vitamina B 6/sangue , Pessoa de Meia-Idade , Inquéritos Nutricionais , Biomarcadores/sangue , Fatores de Risco , Causas de Morte , Idoso de 80 Anos ou mais , Fosfato de Piridoxal/sangue , Ácido Piridóxico/sangueRESUMO
Elevated plasma concentrations of several one-carbon metabolites are associated with increased CVD risk. Both diet-induced regulation and dietary content of one-carbon metabolites can influence circulating concentrations of these markers. We cross-sectionally analysed 1928 patients with suspected stable angina pectoris (geometric mean age 61), representing elevated CVD risk, to assess associations between dietary macronutrient composition (FFQ) and plasma one-carbon metabolites and related B-vitamin status markers (GC-MS/MS, LC-MS/MS or microbiological assay). Diet-metabolite associations were modelled on the continuous scale, adjusted for age, sex, BMI, smoking, alcohol and total energy intake. Average (geometric mean (95 % prediction interval)) intake was forty-nine (38, 63) energy percent (E%) from carbohydrate, thirty-one (22, 45) E% from fat and seventeen (12, 22) E% from protein. The strongest associations were seen for higher protein intake, i.e. with higher plasma pyridoxal 5'-phosphate (PLP) (% change (95 % CI) 3·1 (2·1, 4·1)), cobalamin (2·9 (2·1, 3·7)), riboflavin (2·4 (1·1, 3·7)) and folate (2·1 (1·2, 3·1)) and lower total homocysteine (tHcy) (-1·4 (-1·9, -0·9)) and methylmalonic acid (MMA) (-1·4 (-2·0, -0·8)). Substitution analyses replacing MUFA or PUFA with SFA demonstrated higher plasma concentrations of riboflavin (5·0 (0·9, 9·3) and 3·3 (1·1, 5·6)), tHcy (2·3 (0·7, 3·8) and 1·3 (0·5, 2·2)) and MMA (2·0 (0·2, 3·9) and 1·7 (0·7, 2·7)) and lower PLP (-2·5 (-5·3, 0·3) and -2·7 (-4·2, -1·2)). In conclusion, a higher protein intake and replacing saturated with MUFA and PUFA were associated with a more favourable metabolic phenotype regarding metabolites associated with CVD risk.
Assuntos
Angina Estável , Dieta , Complexo Vitamínico B , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Transversais , Idoso , Angina Estável/sangue , Complexo Vitamínico B/sangue , Complexo Vitamínico B/administração & dosagem , Nutrientes , Biomarcadores/sangue , Proteínas Alimentares/administração & dosagem , Fosfato de Piridoxal/sangue , Gorduras na Dieta/administração & dosagem , Carboidratos da Dieta/administração & dosagem , Ácido Metilmalônico/sangue , Vitamina B 12/sangueRESUMO
PURPOSE: The study aimed to define the clinical, biochemical and genetic features of adult patients with osteopenia/osteoporosis and/or bone fragility and low serum alkaline phosphatase (sALP). METHODS: Twenty-two patients with at least two sALP values below the reference range were retrospectively enrolled after exclusion of secondary causes. Data about clinical features, mineral and bone markers, serum pyridoxal-5'-phosphate (PLP), urine phosphoethanolamine (PEA), lumbar and femur bone densitometry, and column X-ray were collected. Peripheral blood DNA of each participant was analyzed to detect ALPL gene anomalies. RESULTS: Pathogenic ALPL variants (pALPL) occurred in 23% and benign variants in 36% of patients (bALPL), while nine patients harbored wild-type alleles (wtALPL). Fragility fractures and dental anomalies were more frequent in patients harboring pALPL and bALPL than in wtALPL patients. Of note, wtALPL patients comprised women treated with tamoxifen for hormone-sensitive breast cancer. Mineral and bone markers were similar in the three groups. Mean urine PEA levels were significantly higher in patients harboring pALPL than those detected in patients harboring bALPL and wtALPL; by contrast, serum PLP levels were similar in the three groups. A 6-points score, considering clinical and biochemical features, was predictive of pALPL detection [P = 0.060, OR 1.92 (95% CI 0.972, 3.794)], and more significantly of pALPL or bALPL [P = 0.025, OR 14.33 (95% CI 1.401, 14.605)]. CONCLUSION: In osteopenic/osteoporotic patients, single clinical or biochemical factors did not distinguish hypophosphatasemic patients harboring pALPL or bALPL from those harboring wtALPL. Occurrence of multiple clinical and biochemical features is predictive of ALPL anomalies, and, therefore, they should be carefully identified. Tamoxifen emerged as a hypophosphatasemic drug.
Assuntos
Fosfatase Alcalina/genética , Biomarcadores/análise , Hipofosfatemia , Fosfatase Alcalina/análise , Fosfatase Alcalina/sangue , Biomarcadores/sangue , Densidade Óssea , Doenças Ósseas Metabólicas/sangue , Doenças Ósseas Metabólicas/epidemiologia , Doenças Ósseas Metabólicas/genética , Doença Crônica , Estudos Transversais , Análise Mutacional de DNA , Feminino , Fraturas Ósseas/sangue , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/genética , Humanos , Hipofosfatemia/sangue , Hipofosfatemia/diagnóstico , Hipofosfatemia/epidemiologia , Hipofosfatemia/genética , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Osteoporose/sangue , Osteoporose/epidemiologia , Osteoporose/genética , Polimorfismo de Nucleotídeo Único , Fosfato de Piridoxal/análise , Fosfato de Piridoxal/sangue , Estudos RetrospectivosRESUMO
BACKGROUND AND AIMS: Vitamin B6 is involved in a large spectrum of physiological processes and comprises of the vitamers pyridoxamine (PM), pyridoxal (PL), pyridoxine (PN), and their phosphorylated derivatives including the biological active pyridoxal 5'-phosphate (PLP). While PN toxicity is known to complicate several treatments, PM has shown promise in relation to the treatment of metabolic and age-related diseases by blocking oxidative degradation and scavenging toxic dicarbonyl compounds and reactive oxygen species. We aimed to assess the metabolization of oral PM supplements in a single and three daily dose. MATERIALS AND METHODS: We optimized and validated a method for the quantification of the B6 vitamers in plasma and urine using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Five healthy volunteers were recruited to study PM metabolization after a single oral dose of 200 mg PM or a three daily dose of 67 mg PM. A third protocol was implemented as control for dietary intake. Venous blood samples, 24 h urine and fasted second void urine samples were collected. RESULTS: After a single oral dose of 200 mg PM, plasma PM increased in the first 3 h to a maximum of 2324 ± 266 nmol/L. While plasma PM levels returned to baseline after ~10 h of PM intake, PLP increased to a maximum of 2787 ± 329 nmol/L and reached a plateau. We found a small increase of PN to a maximum of 13.5 ± 2.1 nmol/L; it was nearly undetectable after ~12 h. With a three daily dose of 67 mg PM we observed an increase and decline of plasma PM, PL, and PN concentrations after each PM intake. PLP showed a similar increase as in the single dose protocol and accumulated over time. CONCLUSION: In this study we showed high plasma levels of PM after oral PM supplementation. We found steadily increasing levels of the biologically active PLP, with minimal formation of PN. The B6 vitamer PM is an interesting supplement as an inhibitor of harmful processes in metabolic diseases and for the treatment of vitamin B6 deficiency. CLINICAL TRIAL REGISTRY: The study was approved by the Medical Ethics Committee of Maastricht University (NL) and was registered at ClinicalTrials.gov as NCT02954588.
Assuntos
Suplementos Nutricionais , Piridoxamina/administração & dosagem , Vitamina B 6/sangue , Vitamina B 6/urina , Adulto , Cromatografia Líquida de Alta Pressão , Feminino , Voluntários Saudáveis , Humanos , Masculino , Fosfato de Piridoxal/sangue , Fosfato de Piridoxal/urina , Piridoxamina/sangue , Piridoxamina/urina , Piridoxina/sangue , Piridoxina/urina , Espectrometria de Massas em Tandem , Deficiência de Vitamina B 6/terapiaRESUMO
Acute intermittent porphyria (AIP) is a rare metabolic disease caused by mutations within the hydroxymethylbilane synthase gene. Previous studies have reported increased levels of plasma total homocysteine (tHcy) in symptomatic AIP patients. In this study, we present long-term data for tHcy and related parameters for an AIP patient cohort (n = 37) in different clinical disease-states. In total, 25 patients (68%) presented with hyperhomocysteinemia (HHcy; tHcy > 15 µmol/L) during the observation period. HHcy was more frequent in AIP patients with recurrent disease receiving heme arginate, than in nonrecurrent (median tHcy: 21.6 µmol/L; range: 10-129 vs median tHcy: 14.5 µmol/L; range 6-77). Long-term serial analyses showed a high within-person tHcy variation, especially among the recurrent patients (coefficient of variation: 16.4%-78.8%). HHcy was frequently associated with low blood concentrations of pyridoxal-5'-phosphate and folate, while cobalamin concentration and the allele distribution of the methylene-tetrahydrofolate-reductase gene were normal. Strikingly, 6 out of the 9 recurrent patients who were later included in a regime of givosiran, a small-interfering RNA that effectively reduced recurrent attacks, showed further increased tHcy (median tHcy in 9 patients: 105 µmol/L; range 16-212). Screening of amino acids in plasma by liquid-chromatography showed co-increased levels of methionine (median 71 µmol/L; range 23-616; normal <40), suggestive of acquired deficiency of cystathionine-ß-synthase. The kynunerine/tryptophan ratio in plasma was, however, normal, indicating a regular metabolism of tryptophan by heme-dependent enzymes. In conclusion, even if HHcy was observed in AIP patients receiving heme arginate, givosiran induced an aggravation of the dysregulation, causing a co-increase of tHcy and methionine resembling classic homocystinuria.
Assuntos
Acetilgalactosamina/análogos & derivados , Arginina/deficiência , Heme/deficiência , Hiper-Homocisteinemia/etiologia , Porfiria Aguda Intermitente/tratamento farmacológico , Pirrolidinas/uso terapêutico , Acetilgalactosamina/efeitos adversos , Acetilgalactosamina/uso terapêutico , Adulto , Arginina/uso terapêutico , Cistationina beta-Sintase/genética , Feminino , Ácido Fólico/sangue , Heme/uso terapêutico , Homeostase , Homocisteína/metabolismo , Homocistinúria/complicações , Humanos , Hidroximetilbilano Sintase/sangue , Hidroximetilbilano Sintase/genética , Masculino , Metionina/sangue , Pessoa de Meia-Idade , Porfiria Aguda Intermitente/sangue , Porfiria Aguda Intermitente/complicações , Porfiria Aguda Intermitente/genética , Fosfato de Piridoxal/sangue , Pirrolidinas/efeitos adversos , Adulto JovemRESUMO
Vitamin B6-restricted diets and low plasma pyridoxal 5'-phosphate (PLP) status altered plasma polyunsaturated fatty acids (PUFA) compositions. Evidence suggests the role of gender in the metabolism of vitamin B6 and PUFA. However, no epidemiologic study examined the impact of gender on the relationship between vitamin B6 and PUFA status in adults. Thus, we investigated whether there were gender differences in the association of vitamin B6 intake and plasma PLP concentration with plasma PUFA concentrations and ratios (eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), EPA + DHA, EPA/AA, (EPA + DHA)/AA) in US young/middle-aged adults. In total, 864 participants (20-59 years; 484 men, 380 women) from the National Health and Nutrition Examination Survey (NHANES) 2003-2004 were used for this cross-sectional study. Nutrient intakes were estimated from two 24 h recalls and supplement questionnaires; plasma PLP and PUFA were measured. Multivariate linear regression was utilized to obtain unstandardized (b) and standardized (ß) coefficients. Covariates included demographic, socioeconomic, dietary variables, physical activity level, cigarette smoking status, alcohol consumption, prescription medication use, and BMI. There were significant interactions between gender and PLP on EPA (P-interaction = 0.004), DHA (P-interaction = 0.020), EPA + DHA (P-interaction = 0.010), EPA/AA (P-interaction = 0.002), (EPA + DHA)/AA (P-interaction = 0.004), whereas no interaction between gender and B6 intake existed. In gender-stratified analyses, in men, PLP was positively associated with EPA (ß = 0.138, b = 0.104, p = 0.0004), DHA (ß = 0.101, b = 0.058, p = 0.036), EPA + DHA (ß = 0.125, b = 0.073, p = 0.005), EPA/AA (ß = 0.144, b = 0.099, p = 0.0002), (EPA + DHA)/AA (ß = 0.123, b = 0.068, p = 0.005). However, no associations between PLP and PUFA existed in women. In conclusion, gender differences were found in the relationships between plasma PLP and plasma EPA, DHA, EPA + DHA, EPA/AA, and (EPA + DHA)/AA, with significant direct associations in men only among US young/middle-aged adults.
Assuntos
Ácidos Graxos Insaturados/sangue , Fosfato de Piridoxal/sangue , Fatores Sexuais , Vitamina B 6/administração & dosagem , Complexo Vitamínico B/administração & dosagem , Adulto , Estudos Transversais , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Fatores Socioeconômicos , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: a large number of studies have linked vitamin B6 to inflammation and cardiovascular disease in the general population. However, it remains uncertain whether vitamin B6 is associated with cardiovascular outcome independent of inflammation. METHODS: we measured plasma pyridoxal 5'-phosphate (PLP), as an indicator of vitamin B6 status, at baseline in a population-based prospective cohort of 6249 participants of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study who were free of cardiovascular disease. As indicators of low-grade systemic inflammation, we measured high-sensitivity C-reactive protein and GlycA; Results: median plasma PLP was 37.2 (interquartile range, 25.1-57.0) nmol/L. During median follow-up for 8.3 (interquartile range, 7.8-8.9) years, 409 non-fatal and fatal cardiovascular events (composite outcome) occurred. In the overall cohort, log transformed plasma PLP was associated with the composite outcome, independent of adjustment for age, sex, smoking, alcohol consumption, body mass index (BMI), estimated glomerular filtration rate (eGFR), total cholesterol:high-density lipoprotein (HDL)-cholesterol ratio, and blood pressure (adjusted hazard ratio per increment of log plasma PLP, 0.66; 95% confidence interval (CI), 0.47-0.93). However, adjustment for high-sensitivity C-reactive protein and GlycA increased the hazard ratio by 9% and 12% respectively, to non-significant hazard ratios of 0.72 (95% confidence interval, 0.51-1.01) and 0.74 (95% confidence interval, 0.53-1.05). The association of plasma PLP with cardiovascular risk was modified by gender (adjusted Pinteraction = 0.04). When stratified according to gender, in women the prospective association with cardiovascular outcome was independent of age, smoking, alcohol consumption, high-sensitivity C-reactive protein, and GlycA (adjusted hazard ratio, 0.50, 95% confidence interval, 0.27-0.94), while it was not in men (adjusted hazard, 0.99, 95% confidence interval, 0.65-1.51). CONCLUSIONS: in this population-based cohort, plasma PLP was associated with cardiovascular outcome, but this association was confounded by traditional risk factors and parameters of inflammation. Notably, the association of low plasma PLP with high risk of adverse cardiovascular outcome was modified by gender, with a stronger and independent association in women.
Assuntos
Doenças Cardiovasculares/epidemiologia , Estado Nutricional , Deficiência de Vitamina B 6/complicações , Vitamina B 6/sangue , Adulto , Idoso , Proteína C-Reativa/análise , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Feminino , Glicoproteínas/sangue , Fatores de Risco de Doenças Cardíacas , Humanos , Inflamação , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/etiologia , Falência Renal Crônica/prevenção & controle , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fosfato de Piridoxal/sangue , Fatores Sexuais , Deficiência de Vitamina B 6/sangueRESUMO
BACKGROUND: Riboflavin is required to generate the active form of vitamin B-6 (pyridoxal 5'-phosphate; PLP) in tissues, but the relevance of this metabolic interaction for nutritional status of vitamin B-6 is unclear because riboflavin biomarkers are rarely measured in human studies. OBJECTIVES: The purpose of this study was to identify the determinants of biomarkers of vitamin B-6 and riboflavin status and to examine the relationship between these nutrients in healthy adults. METHODS: Multiple linear regression was performed on observational data in 407 healthy adults aged 18-92 y who did not use B-vitamin supplements. Vitamin B-6 status was assessed by plasma PLP concentrations and erythrocyte glutathione reductase activation coefficient (EGRac) was used as a functional indicator of riboflavin status. RESULTS: Dietary intakes of vitamin B-6 and riboflavin were below the average requirements in 10% and 29% of participants, respectively. Suboptimal status of vitamin B-6 (PLP ≤30.0 nmol/L) was more prevalent in adults aged ≥60 y than in younger participants (i.e., 14% compared with 5%), whereas a high proportion (i.e., overall 37%) of both age groups had deficient riboflavin status (EGRac ≥1.40). In multiple regression analysis, EGRac (P = 0.019) was a significant determinant of plasma PLP, along with dietary vitamin B-6 intake (P = 0.003), age (P < 0.001), BMI (kg/m2) (P = 0.031), and methylenetetrahydrofolate reductase gene (MTHFR) genotype (P < 0.001). Significant determinants of EGRac were dietary riboflavin intake (P < 0.001), age (P < 0.001) and MTHFR genotype (P = 0.020). Plasma PLP showed a stepwise decrease across riboflavin status categories from optimal (EGRac ≤1.26) to low (EGRac 1.27-1.39) to deficient status (P = 0.001), independent of dietary vitamin B-6 intake. CONCLUSIONS: The findings are consistent with the known metabolic dependency of vitamin B-6 on riboflavin status and indicate that riboflavin may be the limiting nutrient, particularly in older people, for maintaining adequate vitamin B-6 status.
Assuntos
Riboflavina/administração & dosagem , Vitamina B 6/administração & dosagem , Adulto , Idoso , Envelhecimento , Dieta , Humanos , Estilo de Vida , Pessoa de Meia-Idade , Fosfato de Piridoxal/sangue , Fosfato de Piridoxal/metabolismo , Adulto JovemRESUMO
The pathophysiology of sickle cell disease (SCD) includes vasculopathy as well as anaemia. Elevated plasma homocysteine is a risk factor for vascular disease and may be associated with increased risk of vascular complications in SCD patients. In the present study, microvascular characteristics were assessed in the bulbar conjunctiva of 18 paediatric and 18 adult SCD patients, using the non-invasive technique of computer-assisted intravital microscopy. A vasculopathy severity index (SI) was computed to quantify the degree of microvasculopathy in each patient. Plasma homocysteine and several of its determinants [serum folate and vitamin B12, plasma pyridoxal-5'-phosphate (vitamin B6 status) and creatinine (kidney function)] were measured. Age was strongly correlated with microvasculopathy in the SCD patients, with the SI increasing about 0·1 unit per one-year increase in age (P < 0·001). After adjusting for age, gender, B-vitamin status and creatinine, homocysteine concentration was directly correlated with severity index (P < 0·05). Age and homocysteine concentration were independent predictors of microvasculopathy in SCD patients. It remains to be determined whether lowering homocysteine concentrations using appropriate B-vitamin supplements (folate and vitamins B12 and B6) - particularly if started early in life - could ameliorate microvasculopathy and its associated complications in SCD patients.
Assuntos
Anemia Falciforme/fisiopatologia , Homocisteína/sangue , Microcirculação , Microangiopatias Trombóticas/etiologia , Adolescente , Adulto , Anemia Falciforme/sangue , Criança , Pré-Escolar , Creatina/sangue , Ácido Fólico/sangue , Humanos , Microscopia Intravital , Pessoa de Meia-Idade , Fosfato de Piridoxal/sangue , Índice de Gravidade de Doença , Microangiopatias Trombóticas/sangue , Microangiopatias Trombóticas/fisiopatologia , Vitamina B 12/sangueRESUMO
A 64-year-old woman developed symptoms of vomiting and tonic-clonic convulsions 9.5 h after eating 50 roasted Ginkgo biloba seeds with 100 g of alcohol. The intravenous administration of pyridoxal phosphate effectively improved the symptoms. Blood samples were collected and stored over 35 h. The assessment of 4'-O-methylpyridoxine and vitamin B6 vitamers indicated high levels of both, but the pyridoxal phosphate levels were low during the acute stage. These results suggest that 4'-O-methylpyridoxine inhibits the transformation of vitamin B6 analogues to the active form, pyridoxal phosphate. In our case, alcohol may have extended the period until ginkgo intoxication appeared.
Assuntos
Bebidas Alcoólicas/efeitos adversos , Epilepsia Tônico-Clônica/induzido quimicamente , Ginkgo biloba/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Fosfato de Piridoxal/sangue , Piridoxina/análogos & derivados , Piridoxina/sangue , Sementes , Vitamina B 6/metabolismo , Vômito/induzido quimicamenteRESUMO
BACKGROUND AND AIMS: The active coenzymes of the water soluble vitamins B1 and B6 (thiamine pyrophosphate (TPP) and pyridoxal-5-phosphate (P5P) respectively) play an important role in numerous bodily functions. The simultaneous analysis of both these analytes is limited to either mass spectrometry based methods or commercial kit suppliers. In this study we developed a novel method for analysis of both TPP and P5P by fluorescence detection. METHODS: Briefly, whole blood samples are precipitated by trichloroacetic acid, and P5P and TPP are both derivatised before separation on a C18-PFP column. The new assay's performance was compared against a recent cycle from an external quality assurance program (RCPAQAP) and the current only existing commercial kit (n = 76). RESULTS: Linearity for both analytes was above 0.99 (r2) up to a concentration range of: 4000 nmol/L (P5P) and 2000 nmol/L (TPP). Precision of the method (intra-day and inter-day) compared against commercial quality control material was below 6% (coefficient of variation). Recovery of both compounds exceeded 90%. Accuracy of the protocol displayed satisfactory results in proficiency testing and had an acceptable level of agreement with the existing current kit method. CONCLUSIONS: Overall, this method provides an economical alternative in routine clinical diagnostic laboratories wishing to perform P5P and TPP analysis.
Assuntos
Fosfato de Piridoxal/sangue , Tiamina Pirofosfato/sangue , Cromatografia Líquida de Alta Pressão , Humanos , Garantia da Qualidade dos Cuidados de Saúde , Espectrometria de FluorescênciaRESUMO
Low serum alkaline phosphatase (sALP)-hypophosphatasemia-is a characteristic of hypophosphatasia (HPP), but related to several clinical conditions. Here, we evaluated the frequency, persistency and the etiology of hypophosphatasemia in children. In retrospective analyses of sALP measurements from children, evaluated according to in-house constructed age- and sex-specific reference ranges, patients with no normal sALP measurement (Unresolved hypophosphatasemia) were invited for reanalysis. Prospectively, ALP substrates, pyridoxal-5-phosphate (PLP), and phosphoethanolamine (PEA) were measured in patients with persistent hypophosphatasemia. Radiographs and ALPL gene sequencing for HPP were performed to the cases with elevated PEA and/or PLP. From 130,340 sALP measurements of 93,162 patients, hypophosphatasemia was detected in 1404 samples from 867 patients (0.9%). Among them, 745 had at least one normal sALP values in laboratory records, grouped as transient hypophosphatasemia. 75 out of 122 patients with unresolved hypophosphatasemia could be reanalyzed for sALP, of whom PLP and PEA measurements were required in 37 due to persistent hypophosphatasemia. Both PEA and PLP were elevated in 4 patients, and ALPL gene analysis showed heterozygous mutations in 3 patients and homozygous in 1 patient. Elevated PEA with normal PLP were detected in 3 patients, and one had a heterozygous ALPL mutation. Anemia was the most common diagnosis, and upper respiratory tract infections and chronic diseases were more common in transient and unresolved hypophosphatasemia, respectively. In conclusion, reflected persistent hypophosphatasemia frequency was 1/1552 (0.06%) in this large pediatric cohort and, ALPL gene mutations were detected in 13.5% (5/37) of the studied cases. Although biochemical hypophosphatasemia is not uncommon, clinically significant HPP is rare.
Assuntos
Fosfatase Alcalina , Hipofosfatasia , Fosfatase Alcalina/genética , Criança , Etanolaminas/sangue , Feminino , Heterozigoto , Humanos , Hipofosfatasia/epidemiologia , Masculino , Fosfato de Piridoxal/sangue , Estudos RetrospectivosAssuntos
Cromatografia Líquida de Alta Pressão/métodos , Tiamina/sangue , Vitamina B 6/sangue , Administração Oral , Adulto , Análise Química do Sangue/métodos , Calibragem , Cromatografia Líquida de Alta Pressão/instrumentação , Feminino , Humanos , Masculino , Fosfato de Piridoxal/sangue , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tiamina/administração & dosagem , Tiamina/metabolismo , Tiamina Monofosfato/sangue , Tiamina Pirofosfato/sangue , Vitamina B 6/metabolismoRESUMO
Schistosomes are parasitic platyhelminths that currently infect >200 million people globally. The adult worms can live within the vasculature of their hosts for many years where they acquire all nutrients necessary for their survival and growth. In this work we focus on how Schistosoma mansoni parasites acquire and metabolize vitamin B6, whose active form is pyridoxal phosphate (PLP). We show here that live intravascular stage parasites (schistosomula and adult males and females) can cleave exogenous PLP to liberate pyridoxal. Of the three characterized nucleotide-metabolizing ectoenzymes expressed at the schistosome surface (SmAP, SmNPP5, and SmATPDase1), only SmAP hydrolyzes PLP. Heat-inactivated recombinant SmAP can no longer cleave PLP. Further, parasites whose SmAP gene has been suppressed by RNAi are significantly impaired in their ability to cleave PLP compared to controls. When schistosomes are incubated in murine plasma, they alter its metabolomic profile-the levels of both pyridoxal and phosphate increase over time, a finding consistent with the action of host-exposed SmAP acting on PLP. We hypothesize that SmAP-mediated dephosphorylation of PLP generates a pool of pyridoxal around the worms that can be conveniently taken in by the parasites to participate in essential, vitamin B6-driven metabolism. In addition, since host PLP-dependent enzymes play active roles in inflammatory processes, parasite-mediated cleavage of this metabolite may serve to limit parasite-damaging inflammation. In this work we also identified schistosome homologs of enzymes that are involved in intracellular vitamin B6 metabolism. These are pyridoxal kinase (SmPK) as well as pyridoxal phosphate phosphatase (SmPLP-Ph) and pyridox(am)ine 5'-phosphate oxidase (SmPNPO) and cDNAs encoding these three enzymes were cloned and sequenced. The three genes encoding these enzymes all display high relative expression in schistosomula and adult worms suggestive of robust vitamin B6 metabolism in the intravascular life stages.
Assuntos
Fosfatase Alcalina/metabolismo , Fosfato de Piridoxal/sangue , Schistosoma mansoni/metabolismo , Vitamina B 6/metabolismo , Fosfatase Alcalina/genética , Sequência de Aminoácidos , Animais , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Masculino , Camundongos , Fosfatos/sangue , Monoéster Fosfórico Hidrolases/sangue , Monoéster Fosfórico Hidrolases/genética , Fosforilação , Filogenia , Piridoxal/sangue , Piridoxal Quinase/sangue , Piridoxal Quinase/genética , Fosfato de Piridoxal/metabolismo , Piridoxaminafosfato Oxidase/sangue , Piridoxaminafosfato Oxidase/genética , Interferência de RNA , Proteínas Recombinantes , Schistosoma mansoni/enzimologia , Schistosoma mansoni/genética , Schistosoma mansoni/crescimento & desenvolvimento , Alinhamento de SequênciaRESUMO
BACKGROUND: Plasma concentrations of most vitamins decrease as part of the systemic inflammatory response (SIR). Thus low plasma values do not necessarily indicate deficiency. Vitamin B6 status is usually assessed by measurement of pyridoxal phosphate (PLP) in plasma, although vitamin concentrations in blood cells tend to be better markers of cellular stores. In health, plasma PLP appears to be determined primarily by intake, its binding to albumin, and its hydrolysis by alkaline phosphatase (ALP). OBJECTIVE: To examine, using in vitro studies, the effect of albumin concentration and ALP activity on PLP concentration in plasma and red blood cells of healthy subjects (HS) and critically ill patients (CI). DESIGN: Heparin and EDTA (ALP inhibited) whole blood samples from HS (n = 8) and CI (n = 26) were incubated with PLP. Concentration of PLP in plasma and red cells was measured. Albumin and ALP levels were determined in plasma. RESULTS: In PLP incubated heparin samples, there was a strong direct relationship between albumin in the concentration range 10-44 g/L and increase in plasma PLP concentration (rs = 0.93, P < 0.001) and an inverse relationship with increase in red cell PLP concentration (rs = -0.90, P < 0.001). In contrast, ALP activity was inversely associated with increase in plasma PLP concentration (rs = -0.42; P = 0.013) and directly associated with red cell PLP concentration (rs = 0.49; P = 0.003). CONCLUSIONS: Plasma albumin concentration and to a lesser extent ALP activity influences PLP concentration in plasma and red cells. In conditions associated with low albumin (e.g. SIR) or altered ALP activity, red cell PLP measurements are more likely to be reliable than plasma measurements in differentiating true from apparent vitamin B6 deficiency and to guide vitamin B6 supplementation.
Assuntos
Fosfatase Alcalina/sangue , Eritrócitos/química , Fosfato de Piridoxal/sangue , Albumina Sérica/análise , Deficiência de Vitamina B 6/sangue , Vitamina B 6/sangue , Adulto , Idoso , Coleta de Amostras Sanguíneas/métodos , Estado Terminal , Humanos , Inflamação/sangue , Pessoa de Meia-Idade , Estado NutricionalRESUMO
BACKGROUND: Hypophosphatasia (HPP) is a rare metabolic bone disorder caused by mutations in the alkaline phosphatase (ALPL) gene, and characterized by low circulating alkaline phosphatase (ALP) levels and bone, muscle, dental and systemic manifestations. In this case series we investigate the clinical spectrum, genetic and biochemical profile of adult HPP patients from the University Hospitals Leuven, Belgium. METHODOLOGY: Adults with HPP were identified through medical record review. Inclusion criteria were: (1) age ≥ 16 yr; (2) consecutively low ALP levels not explained by secondary causes; (3) one or more of the following supporting criteria: biochemical evidence of elevated enzyme substrates; subtrochanteric fractures, metatarsal fractures or other typical clinical features; family history of HPP; a known or likely pathogenic ALPL mutation. RESULTS: Nineteen patients met our inclusion criteria (nâ¯=â¯2 infantile, nâ¯=â¯6 childhood, nâ¯=â¯10 adult-onset HPP and one asymptomatic carrier). Fractures and dental abnormalities were the most reported symptoms. Fatigue was reported in nâ¯=â¯7/19 patients (37%), three of which had previously been misdiagnosed as having chronic fatigue syndrome and/or fibromyalgia. Empirical pyridoxine therapy in four patients (without seizures) did not provide symptomatic relief. Nâ¯=â¯7/19 patients (37%) were inappropriately treated or planned to be treated with antiresorptive treatment. Two patients developed atypical femoral fractures following exposure to bisphosphonates and/or denosumab. Patients detected by screening were less severely affected, while patients with homozygous or compound heterozygous mutations had the most severe symptoms, significantly lower circulating ALP levels (pâ¯=â¯0.013) and significantly higher pyridoxal-5'-phosphate (pâ¯=â¯0.0018) and urinary phosphoethanolamine (pâ¯=â¯0.0001) concentrations. CONCLUSIONS: Screening may detect mainly less severely affected individuals, which may nevertheless avoid misdiagnosis and inappropriate antiresorptive drug exposure. Patients with biallelic mutations had more severe symptoms, significantly lower ALP and higher substrate levels. Whether the latter finding has implications for the classification and treatment of HPP should be investigated further in larger cohorts.
Assuntos
Fosfatase Alcalina/genética , Etanolaminas/urina , Fraturas Ósseas/fisiopatologia , Hipofosfatasia/metabolismo , Fosfato de Piridoxal/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Fosfatase Alcalina/metabolismo , Conservadores da Densidade Óssea/efeitos adversos , Denosumab/efeitos adversos , Difosfonatos/efeitos adversos , Epilepsia/tratamento farmacológico , Epilepsia/etiologia , Epilepsia/fisiopatologia , Fadiga/etiologia , Fadiga/fisiopatologia , Feminino , Fraturas do Fêmur/induzido quimicamente , Fraturas do Fêmur/etiologia , Fraturas do Fêmur/fisiopatologia , Fraturas não Consolidadas/etiologia , Fraturas não Consolidadas/fisiopatologia , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/fisiopatologia , Fraturas do Quadril/etiologia , Fraturas do Quadril/fisiopatologia , Humanos , Hipofosfatasia/complicações , Hipofosfatasia/genética , Hipofosfatasia/fisiopatologia , Cálculos Renais/etiologia , Cálculos Renais/fisiopatologia , Masculino , Ossos do Metatarso/lesões , Pessoa de Meia-Idade , Piridoxina/uso terapêutico , Raquitismo Hipofosfatêmico/etiologia , Raquitismo Hipofosfatêmico/fisiopatologia , Índice de Gravidade de Doença , Perda de Dente/etiologia , Perda de Dente/fisiopatologia , Complexo Vitamínico B/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: Vitamin B-6 status is routinely measured as pyridoxal 5'-phosphate (PLP) in plasma. Low concentrations of PLP are associated with rheumatic, cardiovascular, and neoplastic diseases. We have previously shown that vitamin B-6 status affects the kynurenine (Kyn) pathway of tryptophan (Trp) catabolism. OBJECTIVE: This study aimed to comprehensively evaluate the use of Kyns as potential markers of functional vitamin B-6 status across 2 large cohorts. METHODS: We measured circulating concentrations of the first 6 metabolites in the Trp catabolic pathway by LC-MS-MS in the community-based Hordaland Health Study (HUSK; n = 7017) and cardiovascular patient-based Western Norway Coronary Angiography Cohort (WECAC; n = 4161). Cross-sectional and longitudinal associations of plasma PLP with Kyns were estimated using linear and nonlinear regression-based methods. RESULTS: 3'-Hydroxykynurenine (HK), a substrate, and all 4 products formed directly by the PLP-dependent enzymes kynurenine transaminase and kynureninase contributed to the explanation of circulating PLP in multivariable-adjusted regression models. The construct HK:(kynurenic acid + xanthurenic acid + 3'-hydroxyanthranilic acid + anthranilic acid), termed HK ratio (HKr), was related to plasma PLP with standardized regression coefficients (95% CIs) of -0.47 (-0.49, -0.45) and -0.46 (-0.49, -0.43) in HUSK and WECAC, respectively. Across strata of cohort and sex, HKr was 1.3- to 2.7-fold more sensitive, but also 1.7- to 2.9-fold more specific to changes in PLP than a previously proposed marker, HK:xanthurenic acid. Notably, the association was strongest at PLP concentrations < â¼20 nmol/L, a recognized threshold for vitamin B-6 deficiency. Finally, PLP and HKr demonstrated highly sex-specific and corroborating associations with age. CONCLUSIONS: The results demonstrate that by combining 5 metabolites in the Kyn pathway into a simple index, HKr, a sensitive and specific indicator of intracellular vitamin B-6 status is obtained. The data also underscore the merit of evaluating alterations in Kyn metabolism when investigating vitamin B-6 and health.
Assuntos
Doenças Cardiovasculares/sangue , Triptofano/metabolismo , Vitamina B 6/sangue , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/metabolismo , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Cinurenina/sangue , Masculino , Pessoa de Meia-Idade , Fosfato de Piridoxal/sangue , Vitamina B 6/metabolismoRESUMO
BACKGROUND: A frequent observation in inflammatory conditions, including rheumatoid arthritis (RA), is low circulating amounts of pyridoxal 5'-phosphate (PLP), the metabolically active form of vitamin B-6. Recently, a functional marker of vitamin B-6 status, the ratio of 3-hydroxykynurenine (HK): xanthurenic acid (XA) in plasma (HK: XA), was proposed. OBJECTIVE: We investigated vitamin B-6 status in patients with RA before and after established treatment with TNFα inhibitors. METHODS: We performed a longitudinal study of RA patients (n = 106, 36% men, median age 54 y) starting first treatment with a TNFα inhibitor (infliximab, etanercept, adalimumab, golimumab, or certolizumab). Clinical assessment (Disease Activity Score for 28 standard joints, DAS28), joint ultrasonography, and blood draw were performed at baseline and after 3 mo treatment. Plasma concentrations of PLP, HK, and XA were measured by liquid chromatography-tandem mass spectrometry. Associations of changes in vitamin B-6 markers with change in DAS28 were assessed by generalized additive models regression and with European League Against Rheumatism (EULAR) response categories by linear regression. RESULTS: At baseline PLP was inversely correlated with CRP (ρ = -0.27, P = 0.007), whereas HK: XA correlated with DAS28 (ρ = 0.46, P < 0.001), CRP (ρ = 0.36, P < 0.001), and ultrasonography scores (ρ = 0.29-0.35, P ≤ 0.003). After 3 mo treatment, the change (a 33% overall reduction) in DAS28 was related to changes in both PLP (ß = -0.28, P = 0.01) and HK: XA (ß = 0.33, P < 0.001). Good responders (45%) according to EULAR criteria experienced a 31% increase in PLP (P = 0.003) and an 11% decrease in HK: XA (P = 0.1), whereas nonresponders (24%) experienced a 25% increase in HK: XA (P = 0.02). CONCLUSION: Two independent measures of vitamin B-6 status confirm an association with disease activity in RA patients. The association of HK: XA with disease activity may also imply perturbations in kynurenine metabolism in RA. This trial was registered at helseforskning.etikkom.no as 2011/490.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Estado Nutricional , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Deficiência de Vitamina B 6/complicações , Vitamina B 6/sangue , Adulto , Artrite Reumatoide/sangue , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Feminino , Humanos , Cinurenina/análogos & derivados , Cinurenina/sangue , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fosfato de Piridoxal/sangue , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangue , Deficiência de Vitamina B 6/sangue , Xanturenatos/sangueRESUMO
BACKGROUND: Vitamin B-6 (B-6), in the form of pyridoxal 5'phosphate (PLP), is critical for one-carbon metabolism reactions and cellular function. Plasma PLP concentration decreases throughout pregnancy, but the functional consequences of this have not been studied. Plasma cystathionine is a sensitive indicator of suboptimal B-6 status in healthy adults. OBJECTIVES: The aim of this study was to determine the relation between plasma PLP and cystathionine concentrations, and to assess longitudinal changes in plasma concentrations of metabolites of one-carbon metabolism, including total homocysteine (tHcy), cysteine, methionine, glycine, serine, and glutathione, over the course of pregnancy. DESIGN: This was a prospective cohort study of 186 healthy Brazilian pregnant women (20-40 y). Plasma PLP and metabolite concentrations were quantified in fasting maternal blood samples collected between 5-13, 20-26, and 30-36 weeks of gestation. Linear mixed regression models were used to determine the association of 1) first-trimester PLP tertiles, and 2) the variation of PLP concentration throughout pregnancy, with related metabolite concentrations across weeks of gestation. RESULTS: Median (IQR) PLP concentration decreased from 36.2 (29.2-44.5) to 21.0 (15.9-26.0) to 16.8 (12.9-21.4) nmol/L in the first, second, and third trimester, respectively, whereas cystathionine concentration increased from 63.2 (49.7-78.9) to 122 (98.0-167) to 143 (114-193) nmol/L, respectively (both P < 0.001). The variation of PLP throughout pregnancy was inversely associated with cystathionine concentration across weeks of gestation, after adjusting for confounding factors; ß (95% CI) = -0.387 (-0.752, -0.219), P = 0.04. This association significantly differed by trimester and was strongest in the third trimester. Plasma concentrations of glycine, serine, methionine, cysteine, and tHcy decreased, and that of glutathione increased, between the first and second trimesters (all P < 0.05). CONCLUSIONS: The variation of PLP concentration predicted cystathionine concentration throughout pregnancy. Increases in plasma cystathionine across trimesters may reflect maternal intracellular B-6 deficiency.
Assuntos
Cistationina/sangue , Trimestres da Gravidez , Fosfato de Piridoxal/sangue , Adulto , Feminino , Humanos , Gravidez , Estudos Prospectivos , Vitamina B 6/sangue , Adulto JovemRESUMO
Hypophosphatasia (HPP) is a rare inherited disorder of bone and mineral metabolism caused by loss of function mutations in the ALPL gene. The presentation in children and adults can be extremely variable and natural history is poorly understood particularly in adults. Careful patient evaluation is required with consideration of pharmacologic intervention in individuals meeting criteria for therapy. INTRODUCTION: The purposes of this review are to present current evidence regarding the diagnosis and management of hypophosphatasia in children and adults and provide evidence-based recommendations for management. METHOD: A MEDLINE, EMBASE, and Cochrane database search and literature review was completed. The following consensus recommendations were developed based on the highest level of evidence as well as expert opinion. RESULTS: Hypophosphatasia is a rare inherited disorder of bone and mineral metabolism due to loss of function mutations in the tissue non-specific alkaline phosphatase (ALPL) gene causing reductions in the activity of the tissue non-specific isoenzyme of alkaline phosphatase (TNSALP). Deficient levels of alkaline phosphatase result in elevation of inhibitors of mineralization of the skeleton and teeth, principally inorganic pyrophosphate. The impaired skeletal mineralization may result in elevations in serum calcium and phosphate. Clinical features include premature loss of teeth, metatarsal and subtrochanteric fractures as well as fragility fractures. Poor bone healing post fracture has been observed. Myalgias and muscle weakness may also be present. In infancy and childhood, respiratory and neurologic complications can occur. CONCLUSIONS: HPP is associated with significant morbidity and mortality. Pharmacologic intervention can result in significant clinical improvement. This Canadian position paper provides an overview of the musculoskeletal, renal, dental, respiratory, and neurologic manifestations of hypophosphatasia. The current state of the art in the diagnosis and management of hypophosphatasia is presented.