Hungarian consensus recommendation on the role of vitamin D in disease prevention and treatment / Magyarországi konszenzusajánlás a D-vitamin szerepérol a betegségek megelozésében és kezelésében

Nine Hungarian medical societies have developed a consensus recommendation on the preferred normal range of vitamin D, the dose of vitamin D supplementation and the method of administration. They summarized the clinical conditions and diseases the development of which may be associated with vitamin D deficiency (VDD). VDD is extremely common in Hungary, especially in late winter. The lower limit of the recommended normal range is 75 nmol/l, although the clinical significance of deficiency is evident mainly at values below 50 nmol/l, but since vitamin D supplementation at the recommended dose is safe, it is worthwhile for everyone to reduce the health risk associated with VDD. The aim of vitamin D supplementation is to prevent deficiency. The recommended normal range is 75­125 nmol/l, above which there is no clear benefit of vitamin D supplementation. To maintain the normal range, a daily intake of 2000 IU in adults is recommended during the UV-B radiation-free period. Vitamin D supplementation is also recommended for children during the same periods and conditions as for adults, but the dose varies with age. In adults, vitamin D3 supplementation at daily, weekly and monthly intervals is equally effective and safe. In severe deficiency, a loading dose is recommended, followed by maintenance supplementation. In addition to the wellknown skeletal, immunological and oncological effects of VDD, more and more data support unfavorable gyneco- logical and obstetric effects. The process of building the consensus has met the requirements of the latest Delphi criteria.

Analytical, experimental and clinical aspects of total 25-hydroxyvitamin D measurement by two ligand assays are differentially biased by disease-related factors.

BACKGROUND: Pathological concentrations of plasma proteins may confound the results of binding assays. We compared two routinely used total 25-hydroxyvitamin D [t-25(OH)D] methods: a chemiluminescence-immuno-(CLIA) and an electro-chemiluminescence-protein-binding-(ECLPBA) assay. METHODS: Two sub-studies were performed: 1) In an "in vitro" study, exogenous albumin was added to pools of patients' sera with low albumin levels; and 2) In "ex vivo" studies of Cohort_1: sera of hospitalized patients with low albumin levels, and of healthy controls; and of Cohort_2: outpatients with chronic kidney disease in pre-dialysis stage, or on peritoneal dialysis and hemodialysis were investigated by the routine and LC_MS/MS methods. RESULTS: When increasing albumin concentrations were "in vitro" added, t-25(OH)D levels were overestimated by ECLPBA, and underestimated by CLIA. In patients' sera, positive correlations were detected between t-25(OH)D-vitamin D binding protein (DBP) values by both routine methods, and between t-25(OH)D-albumin values by all three methods. Much higher t-25(OH)D was measured by LC_MS/MS in all subgroups. When altering albumin levels with constant DBP concentration, the "in vitro" experiment revealed a higher sensitivity of ECLPBA. The "ex vivo" measurements demonstrated clinically relevant differences between the routine methods. CONCLUSION: Both routine methods are dependent of the matrix effect in hospitalized patients, which is predicted by the DBP/Albumin ratios. In hemodialysis, ECLPBA is recommended because its outcomes differ less from those of LC_MS/MS. The results of LC_MS/MS are reliable, but not routinely available. A guidance would be valuable on how levels measured by the binding methods differ from those by LC-MS/MS in various clinical conditions.

Genetic variants of VDR and CYP2R1 affect BMI independently of serum vitamin D concentrations.

BACKGROUND: Vitamin D metabolism and obesity have been linked by several studies, however the reason for this association is unclear. Our objective was to investigate potential correlations between genetic variants in key enzymes of vitamin D metabolism and the body mass index on a representative and random sample of Hungarian adults. METHODS: Altogether 462 severely vitamin D deficient individuals were studied at the end of winter in order to decrease environmental and maximize any relevant genetic effect. Furthermore, participants with lifestyle factors known to affect vitamin D homeostasis were also excluded. We selected 23 target SNPs in five genes that encode key proteins of vitamin D metabolism (NADSYN1, GC, CYP24A1, CYP2R1, VDR). RESULTS: Variants in 2 genetic polymorphisms; rs2853564 (VDR) and rs11023374 (CYP2R1) showed a significant association with participants' BMI. These associations survived further adjustment for total-, free-, or bioactive-25(OH) vitamin D levels, although the variance explained by these 2 SNPS in BMI heterogeneity was only 3.2%. CONCLUSION: Our results show two novel examples of the relationship between genetics of vitamin D and BMI, highlighting the potential role of vitamin D hormone in the physiology of obesity.

[Evaluation of the epidemiological and clinical characteristics of central nervous system infections in adults in the West Pannonian region]. / A felnottkori neuroinfekciók epidemiológiai és klinikai jellemzoinek vizsgálata a nyugat-dunántúli régióban.

Introduction: Despite advancements in diagnostic capabilities and the availability of effective antimicrobial agents, community-acquired infections of the central nervous system (CNS) are still associated with high mortality rates. Aim: To assess the epidemiological and clinical characteristics of community-acquired CNS infections treated in the West Pannonian region between 2010 and 2016. Method: Clinical data of 176 patients were retrospectively analysed in two age cohorts: 15 to 65 and more than 65 years of age. Results: Neuroinfections were found to be bacterial in 81, viral in 91, parasitic in 1 and mixed in 3 cases during the observation period. The most frequent bacterial pathogens isolated were Streptococcus pneumoniae (20%) and Borrelia burgdorferi (16%). The most frequent viral pathogens isolated were tick-borne encephalitis virus (37%), herpes simplex virus (10%) and enterovirus (7%). Aetiology was unknown in 40 percent of all cases. The average incidence rate was 9.8/100 000 person/year with a mortality rate of 12%. In the cohort of patients aged >65 years, significantly higher frequencies of immunocompromising factors, lower Glasgow Coma Scale values at admission and confusion were observed (p-values: 0.008, 0.017, and 0.050, respectively). Prognosis was negatively influenced by low Glasgow Coma Scale values at admission (OR = 1.6 CI95%: 1.3-1.9; p<0.001), old age (OR = 6.5 CI95%: 2.5-17.1; p<0.001) and immunodeficiency (OR = 3.1 CI95%: 1.2-8.1; p = 0.019). Conclusions: S. pneumoniae remains the most frequently observed causative bacterial pathogen associated with community-acquired CNS infections. Incidence of tick-borne encephalitis in our county is higher than the national average (2.3 versus 0.35/100 000 person/year). Orv Hetil. 2019; 160(40): 1574-1583.

Prognostic Relevance of Circulating 25OHD Fractions for Early Recovery and Survival in Patients with Hip Fracture †.

The relation between vitamin-D (VD) status and healing after hip fracture had not been sufficiently addressed. Currently serum total 25-hydroxy-VD (t-25OHD) is the most widely used indicator of VD status. It is unclear whether free or bioavailable VD are better markers of 25OHD availability for tissues. Validity of overall cut-off values of t-25OHD is limited. OBJECTIVES: (1) Assess serum levels of circulating forms of 25OHD in patients with hip fracture (PwHF: N = 199) compared to active controls without history of fracture (N = 102); (2) determine relationship between 25OHD fractions and functional performance after surgery (FPAS) and survival. The t-25OHD; VD binding protein and albumin levels were measured. Comorbidities; lifestyle; FPAS and survival were recorded at seven months. VD deficiency occurred more frequently in PwHF than in controls (72% vs. 38%). Patients with better FPAS showed higher 25OHD in all fractions than with poor FPAS. Controlled by lifestyle; 25OHD levels were independent predictive factors (p < 0.001). Good FPAS values forecasted longer survival (OR: 6.5CI:3.2⁻13.3; p < 0.0001). All 25OHD forms showed a tendency to predict survival. Mortality rate decreased to 8% in individuals with t-25OHD levels of >22.6⁻39.5 nmol/L and increased to 14% with >40 nmol/L. These observations highlight the importance of serum 25OHD assessment and moderate VD substitution for healing and survival.

Impact of genetic influence on serum total- and free 25-hydroxyvitamin-D in humans.

Serum 25-hydroxyvitamin D /25OHD/ levels in humans are determined primarily by environmental factors such as UV-B radiation and diet, including vitamin D intake. Although some genetic determinants of 25OHD levels have been shown, the magnitude of this association has not yet been clarified. The present study evaluates the genetic contribution to total- /t-25OHD/ and free-25OHD /f-25OHD/ in a representative sample of the Hungarian population (n = 462). The study was performed at the end of winter to minimize the effect of sunlight, which is a major determinant of serum vitamin D levels. Single nucleotide polymorphisms (SNPs) of five genes playing major roles in vitamin D metabolism were investigated (NADSYN1, DHCR7, GC, CYP2R1 and CYP24A1). The selected SNPs account for 13.1% of the variance of t-25OHD levels. More than half of the genetic effect on t-25OHD levels was explained by two polymorphisms (rs7935125 in NADSYN1 and rs2762941 in CYP24A1), which had not previously been investigated with respect to vitamin D metabolism. No SNPs exhibited association with f-25OHD levels. Unexpectedly, SNPs that showed univariate associations with vitamin D binding protein (DBP) levels were not associated with f-25OHD levels questioning the biological significance of these polymorphisms. The present study shows that t-25OHD levels are significantly influenced by genetic factors, however, the clinical significance of this observation remains to be defined, as variation in f-25OHD levels are marginally explained by genetic effects.

[Vitamin D and calcium supplementation in elderly patients with hip fracture]. / D-vitamin és kalciumpótlás az idoskori csípotáji törések megelozésében.

Vitamin D plays an important role in maintaining calcium and bone metabolism, a risk factor of osteoporosis, fall and fracture in old age. Reduction in D-vitamin levels associated with compensatory increased level of parathyroid hormone causes significant loss of bone matrix, so substitutions of vitamin D and calcium are very important. Many authors publish their recommended doses used for prevention of hip fracture during the last years. Some authors are satisfied only with vitamin D supplementation while others have better experiences with vitamin D and calcium substitution. On the other hand, some metaanalyses give contradictory results and propose further investigations. It is important to consider the patients' eating habits and lifestyle as well as the risk of cardiovascular and other chronic diseases. Further trials should be done in different age groups in order to examine the effects of different doses of vitamin D without and with calcium to make a final decision. Orv Hetil. 2017; 158(43): 1699-1707.

The role of serum total and free 25-hydroxyvitamin D and PTH values in defining vitamin D status at the end of winter: a representative survey.

We sought the lowest serum total 25-hydroxyvitamin D (t-25OHD) values in geographic areas with four seasons and investigated whether the calculation of serum free 25-hydroxyvitamin D (f-25OHD) could provide additional information on vitamin D status. This is a representative, cross-sectional study restricted to a sampling period at the end of winter, using a non-probability, stratified sample of the adult community-dwelling Hungarian population (n = 882). We measured t-25OHD, vitamin D binding protein (DBP), parathyroid hormone (PTH), and albumin levels. f-25OHD concentrations were calculated. We assessed environmental factors that could affect vitamin D levels and diseases possibly related to vitamin D deficiency. Mean t-25OHD values of the total population were 41.3 ± 20.6 nmol/L. t-25OHD levels were below 75, 50, and 30 nmol/L in 97, 77, and 34 % of participants not receiving vitamin D supplementation, respectively. t-25OHD values weakly positively correlated with DBP (r = 0.174; p = 0.000), strongly with f-25OHD (r = 0.70; p = 0.000). The association between t-25OHD and f-25OHD and between t-25OHD and PTH were non-linear (p squared term = 0.0004 and 0.004, respectively). t-25OHD levels were not affected by gender, age, place of residence; however, they were related to body mass index, sunbed sessions, and tropical travel. In contrast, f-25OHD levels were different in males and females but were not related to obesity. t- and f-25OHD were lower among people with cardiovascular diseases (p = 0.012). Nearly the entire Hungarian population is vitamin D insufficient at the end of winter. The use of t-25OHD could show a spurious association with obesity; however, it does not reflect the obvious sex difference.

Is rectal indomethacin effective in preventing of post-endoscopic retrograde cholangiopancreatography pancreatitis?

AIM: To investigate the effectiveness of rectally administered indomethacin in the prophylaxis of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis and hyperamylasaemia in a multicentre study. METHODS: A prospective, randomised, placebo-controlled multicentre study in five endoscopic units was conducted on 686 patients randomised to receive a suppository containing 100 mg indomethacin, or an inert placebo, 10-15 min before ERCP. Post-ERCP pancreatitis and hyperamylasaemia were evaluated 24 h following the procedure on the basis of clinical signs and laboratory parameters, and computed tomography/magnetic resonance imaging findings if required. RESULTS: Twenty-one patients were excluded because of incompleteness of their data or because of protocol violation. The results of 665 investigations were evaluated: 347 in the indomethacin group and 318 in the placebo group. The distributions of the risk factors in the two groups did not differ significantly. Pancreatitis developed in 42 patients (6.3%): it was mild in 34 (5.1%) and severe in eight (1.2%) cases. Hyperamylaesemia occurred in 160 patients (24.1%). There was no significant difference between the indomethacin and placebo groups in the incidence of either post-ERCP pancreatitis (5.8% vs 6.9%) or hyperamylasaemia (23.3% vs 24.8%). Similarly, subgroup analysis did not reveal any significant differences between the two groups. CONCLUSION: 100 mg rectal indomethacin administered before ERCP did not prove effective in preventing post-ERCP pancreatitis.