Vitamin B12 deficiency: correction of P-methylmalonic acid for estimated glomerular filtration rate to improve diagnostic value - a confirmatory study.

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 <60 mL/min were reclassified as non-deficient. Conclusions: We have demonstrated that correcting P-MMA for eGFR can reclassify P-MMA levels across decision limits for diagnosing B12 deficiency, in particular for patients with reduced kidney function. This may have clinical implications for avoiding overdiagnosis of this chronic disease.

Plasma Vitamin B12 Levels, High-Dose Vitamin B12 Treatment, and Risk of Dementia.

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 (<200 pmol/L) were propensity score-matched 1:1 with patients with normal levels (200-600 pmol/L). We used multivariable Cox regression to compute 0-15-year hazard ratios for dementia. RESULTS: For low P-B12 and normal P-B12 level groups, we included 53,089 patients in the primary P-B12 cohort and 13,656 patients in the secondary B12 treatment cohort. In the P-B12 cohort, hazard ratios for AD centered around one, regardless of follow-up period or treatment during follow-up. In the B12 treatment cohort, risk of AD was unaffected by low pre-treatment P-B12 levels, follow-up period and type of B12 treatment. Findings were similar for all-cause and vascular dementia. CONCLUSION: We found no associatio1n between low P-B12 levels and dementia. Associations were unaffected by B12 treatment. Results do not support routine screening for B12 deficiency in patients with suspected dementia.

Existing Data Sources in Clinical Epidemiology: Laboratory Information System Databases in Denmark.

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.

Vitamin B12 and its binding proteins in patients with non-small cell lung cancer referred to fast-track diagnostic work-up for lung cancer.

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 <.05). We observed no difference in cobalamin or holotranscobalamin levels when comparing patients diagnosed with non-small cell lung cancer (n = 161, 18%) to patients without lung cancer (n = 742, 80%), while transcobalamin showed minor differences. Haptocorrin was significantly higher in those with cancer, mainly among patients with adenocarcinoma (n = 94). A comparison of patients with the highest vs. lowest quartile levels of haptocorrin yielded an adjusted odds ratio for adenocarcinoma of 2.39 (95% confidence interval: 1.26-4.55). However, ROC curve analyzes showed haptocorrin (AUC = 0.55) and total transcobalamin (AUC = 0.56) to be poor diagnostic markers for lung cancer. A high proportion of patients suspected for non-small cell lung cancer showed increased levels of cobalamin-binding proteins. We thereby confirm the association between non-small cell lung cancer and high cobalamin levels and found that haptocorrin was the major underlying factor causing high cobalamin levels. However, none of these biomarkers were of diagnostic use among patients referred for suspected lung cancer.

Elevated plasma vitamin B12 levels and risk of venous thromboembolism among cancer patients: A population-based cohort study.

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 200-600pmol/L) for the risk of VTE before and after the cancer diagnosis date (index date). RESULTS: The risk of cancer-associated VTE 30days after index date increased with higher Cbl levels. The cumulative incidence (95% CI) by Cbl levels was: 200-600pmol/L: 0.24 (0.18-0.31); 601-800pmol/L: 0.63 (0.34-1.09); >800pmol/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.

Elevated plasma vitamin B12 levels and cancer prognosis: A population-based cohort study.

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 200-600 pmol/L (reference/normal range), 601-800 pmol/L and >800 pmol/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: 200-600 pmol/L: 69.3%; 601-800 pmol/L: 49.6%; >800 pmol/L: 35.8%; comparison cohort: 72.6%]. Thirty-day mortality was elevated for patients with Cbl levels of 601-800 pmol/L or >800 pmol/L, compared to patients with levels of 200-600 pmol/L [(MRR (95% confidence interval): 601-800 pmol/L vs. 200-600 pmol/L: 1.9 (1.6-2.2); >800 pmol/L vs. 200-600 pmol/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.