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Background and Purpose Previous studies suggest an association between increased homocysteine (Hcy) and risk of ischemic stroke. Yet, it remains unknown whether a dose-response association exists between Hcy levels and risk of ischemic stroke.Methods Systematic literature searches were performed in PubMed, Embase, Scopus, and Web of Science. Inclusion criteria were studies investigating ischemic stroke risk in an adult population with measured Hcy levels. We computed odds ratios (ORs) for a 5 µmol/L increase in Hcy levels using a random effects meta-analysis.Results In total, 108 studies met the inclusion criteria of which 22 were rated as high-quality studies, and 20 studies included a dose-response analysis. Hcy levels were analyzed either as a continuous or categorical variable. The majority of the studies found an increased risk of ischemic stroke when comparing the highest-to-lowest Hcy strata. A graded association was observed over the Hcy strata, indicating a dose-response association, with the most apparent effect when Hcy levels exceeded approximately 15 µmol/L. No studies explored a potential nonlinear association between Hcy levels and ischemic stroke. Six studies were included in a meta-analysis, showing an OR of 1.43 (95% confidence interval [CI]: 1.28–1.61) per 5 µmol/L increase in Hcy levels.Conclusion This review and meta-analysis indicate a dose-response association between Hcy levels and ischemic stroke. An evident increase in effect measures was observed when Hcy levels exceeded 15 µmol/L, indicating a nonlinear association between ischemic stroke and Hcy levels. This nonlinear association warrants further study.This study is registered with clinical trial ( https://www.crd.york.ac.uk/prospero/ ; unique identifier: CRD42019130371).

Objectives: For diagnosis of vitamin B12 deficiency, plasma methylmalonic acid (P-MMA) is considered superior to plasma vitamin B12 (P-B12). Reduced kidney function elevates P-MMA, hence, hampering P-MMA as a biomarker. We assessed whether correcting P-MMA for estimated glomerular filtration rate (eGFR) can affect the estimated prevalence of B12 deficiency. Methods: We included 115,245 patients with concomitant measurements of P-MMA, P-B12 and P-Creatinine. B12 deficiency was classified using P-MMA decision limits at >0.75 and >0.43 µmol/L. The non-linear relation between eGFR and P-MMA was estimated using spline regression. We calculated the percentage-wise reclassification of B12 deficiency by using an eGFR corrected P-MMA formula with eGFR reference points of 90 and 60 mL/min. Results: 6% with B12 deficiency were reclassified as non-deficient after adjusting for eGFR (reference point eGFR 90 mL/min) with both P-MMA decision limits. Overall B12 deficiency prevalence was reduced from 9.6% to 9.0% (P-MMA decision limit 0.43 µmol/L). With P-MMA decision limits at 0.75 and 0.43 µmol/L, 33.6% and 44.8% of B12 deficient patients with an eGFR

Background: It is controversial whether B12 deficiency causes dementia or B12 treatment can prevent dementia. Objective: To assess associations between low plasma (P-)B12 levels, B12 treatment, and risk of Alzheimer’s disease (AD; primary outcome) and all-cause or vascular dementia (secondary outcomes). Methods: We conducted a population-based cohort study using Danish registry data to assess associations between low P-B12 levels, high-dose injection or oral B12 treatment, and risk of dementia (study period 2000–2013). The primary P-B12 cohort included patients with a first-time P-B12 measurement whose subsequent B12 treatment was recorded. The secondary B12 treatment cohort included patients with a first-time B12 prescription and P-B12 measurement within one year before this prescription. For both cohorts, patients with low P-B12 levels (

Routine biomarker results from hospital laboratory information systems, covering hospitals and general practitioners, in Denmark are available to researchers through access to the regional Clinical Laboratory Information System Research Database at Aarhus University and the nationwide Register of Laboratory Results for Research. This review describes these two data sources. The laboratory databases have different geographical and temporal coverage. They both include individual-level biomarker results that are electronically transferred from laboratory information systems. The biomarker results can be linked to all other Danish registries at the individual level, using the unique identifier, the CPR number. The databases include variables such as the CPR number, date and time (hour and minute) of sampling, NPU code, and name of the biomarker, identification code for the laboratory and the requisitioner, the test result with the corresponding unit, and the lower and upper reference limits. Access to the two databases differs since they are hosted by two different institutions. Data cannot be transferred outside Denmark, and direct access is provided only to Danish institutions. It is concluded that access to data on routine biomarkers expands the detailed biological and clinical information available on patients in the Danish healthcare system. The full potential is enabled through linkage to other Danish healthcare registries.

High cobalamin levels have previously been associated with short-term cancer risk, including lung cancer. We explored whether levels of cobalamin and/or its binding proteins are useful as a diagnostic tool in patients suspected of non-small cell lung cancer. We included 889 patients referred for fast-track diagnosis of lung cancer to Aarhus University Hospital, Denmark. We analyzed plasma concentrations of cobalamin, transcobalamin, holotranscobalamin and haptocorrin. Information on lung cancer diagnosis was retrieved from a national database. The study cohort showed levels above reference intervals for cobalamin 12%, holotranscobalamin 25%, transcobalamin 9% and haptocorrin 36% (all p-values

Routine biomarker results from hospital laboratory information systems, covering hospitals and general practitioners, in Denmark are available to researchers through access to the regional Clinical Laboratory Information System Research Database at Aarhus University and the nationwide Register of Laboratory Results for Research. This review describes these two data sources. The laboratory databases have different geographical and temporal coverage. They both include individual-level biomarker results that are electronically transferred from laboratory information systems. The biomarker results can be linked to all other Danish registries at the individual level, using the unique identifier, the CPR number. The databases include variables such as the CPR number, date and time (hour and minute) of sampling, NPU code, and name of the biomarker, identification code for the laboratory and the requisitioner, the test result with the corresponding unit, and the lower and upper reference limits. Access to the two databases differs since they are hosted by two different institutions. Data cannot be transferred outside Denmark, and direct access is provided only to Danish institutions. It is concluded that access to data on routine biomarkers expands the detailed biological and clinical information available on patients in the Danish healthcare system. The full potential is enabled through linkage to other Danish healthcare registries.

Background Elevated plasma vitamin B12 levels (cobalamin, Cbl) are associated with increased short-term cancer risk among patients referred for this laboratory measurement. We aimed to assess prognosis in cancer patients with elevated plasma Cbl. Methods We conducted a population-based cohort study using data from Danish medical registries during 1998–2014. The study included 25,017 patients with a cancer diagnosis and Cbl levels of 200–600pmol/L (reference/normal range), 601–800pmol/L and >800pmol/L measured up to one year prior to diagnosis, and a comparison cohort of 61,988 cancer patients without a plasma Cbl measurement. Patients treated with Cbl were excluded. Survival probability was assessed using Kaplan–Meier curves. Mortality risk ratios (MRR) were computed using Cox proportional hazard regression, adjusted for age, sex, calendar year, cancer stage and comorbidity, scored using the Charlson comorbidity index. Results Survival probabilities were lower among patients with elevated Cbl levels than among patients with normal levels and among members of the comparison cohort [(1-year survival,%) Cbl: 200–600pmol/L: 69.3%; 601–800pmol/L: 49.6%; >800pmol/L: 35.8%; comparison cohort: 72.6%]. Thirty-day mortality was elevated for patients with Cbl levels of 601–800pmol/L or >800pmol/L, compared to patients with levels of 200–600pmol/L [(MRR (95% confidence interval): 601–800pmol/L vs. 200–600pmol/L: 1.9 (1.6–2.2); >800pmol/L vs. 200–600pmol/L: 2.7 (2.4–3.1)]. This association remained robust for 31–90-day and 91–365-day mortality, showing similar dose-response patterns. Conclusion Cancer patients with elevated Cbl levels had higher mortality than those with normal Cbl levels. These findings may have clinical significance for assessing the prognosis of cancer patients.

Introduction Both venous thromboembolism (VTE) and high plasma vitamin B12 levels (cobalamin, Cbl) are markers of occult cancer and aggressive cancer with a poor prognosis. In this population-based cohort study, we assessed VTE risk among cancer patients with high plasma Cbl levels. Materials and methods We used Danish health registries to identify a Cb1 cohort of 25,310 cancer patients with a plasma Cbl measurement prior to cancer diagnosis. The cohort was subdivided according to Cbl levels (pmol/L): 200–600 (population reference range), 601–800 and > 800. All VTE events were considered provoked and categorised as either cancer-associated if no other provoking factors were present before VTE or provoked by other risk factors (surgery, trauma, or pregnancy). We calculated cumulative incidence proportions and adjusted hazard ratios computed from Cox regression analysis (reference: plasma Cbl of 200–600 pmol/L) for the risk of VTE before and after the cancer diagnosis date (index date). Results The risk of cancer-associated VTE 30 days after index date increased with higher Cbl levels. The cumulative incidence (95% CI) by Cbl levels was: 200–600 pmol/L: 0.24 (0.18–0.31); 601–800 pmol/L: 0.63 (0.34–1.09); > 800 pmol/L: 0.86 (0.49–1.40). Adjusted hazard ratios (95% CI) were: 601–800 vs. 200–600: 2.55 (1.32–4.92); > 800 vs. 200–600: 2.36 (1.19–4.71). We found similar results for VTE provoked by other risk factors and for VTE occurring before index date, but scarcity of events produced uncertain risk estimates. Conclusion We demonstrated an association between high plasma Cbl levels and risk of VTE in cancer patients. Any clinical implications warrant further study.

In Denmark, patients with vitamin B12 deficiency are usually treated for life with either Betolvex or Vibeden given as injections every third month. This case report describes a patient who received injections with vitamin B12 prescribed in Germany. The drug prescribed was not available in Denmark; hence the treatment was unsuccessful after the patient returned to Denmark. This led to extensive diagnosing before the cause for the inadequate treatment was found. It illustrates that different vitamin B12 drugs may result in different treatment outcomes, and that caution should be taken when treating patients with vitamin B12 drugs from other countries.

Background: Recently, the cell-surface receptor involved in the internalisation of the cobalamin(vitamin B12, Cbl) transporting protein, transcobalamin(TC), was described, and was found to be CD320(1). So far, it remains unsolved whether CD320 is present in a soluble form (sCD320) in serum. Our aim was to establish an ELISA for sCD320 and to explore the occurrence of sCD320 in human serum. Methods: In order to develop an ELISA we used an in-house monoclonal antibody as capture antibody, and for detection, a biotin labelled polyclonal antibody (R&D Systems) combined with an avidin based detection system. A medium containing recombinant CD320 (produced in-house) and commercially available CD320 (Abnova) were explored as suitable calibrators. Standard Western blot was performed to ensure the specificity of the capture antibody. Serum from patients referred for measurement of plasma Cbl(measured on Cobas 6000, Roche Diagnostics) and patients with extreme values of serum TC was analysed. Total TC was measured employing an in-house ELISA (2). Results: The Western blot showed a highly specific capture antibody. The ELISA assay showed a curvilinear response for dilutions of the medium/recombinant CD320 0.4-4 nmol/L. For practical reasons medium was used as calibrator. Four serum samples showed dilutions curves comparable to that of the calibrator. Preliminary analysis of patient samples with different Cbl levels showed that sCD320 was present in nine out of 28 (32%) patients with Cbl2000 pmol/L). Conclusions: We have developed an ELISA for measurement of sCD320. Preliminary results show no relation between low plasma cobalamins and the presence of sCD320, but an increased amount of the protein was observed in patients with low or high levels of TC. The possible clinical utility of sCD320 remains to be established .