B₁₂ deficiency is the leading cause of megaloblastic anemia, and although more common in the elderly, can occur at any age. Clinical disease caused by B₁₂ deficiency usually connotes severe deficiency, resulting from a failure of the gastric or ileal phase of physiological B₁₂ absorption, best exemplified by the autoimmune disease pernicious anemia. There are many other causes of B₁₂ deficiency, which range from severe to mild. Mild deficiency usually results from failure to render food B₁₂ bioavailable or from dietary inadequacy. Although rarely resulting in megaloblastic anemia, mild deficiency may be associated with neurocognitive and other consequences. B₁₂ deficiency is best diagnosed using a combination of tests because none alone is completely reliable. The features of B₁₂ deficiency are variable and may be atypical. Timely diagnosis is important, and treatment is gratifying. Failure to diagnose B₁₂ deficiency can have dire consequences, usually neurological. This review is written from the perspective of a practicing hematologist.

Folate, an essential nutrient found naturally in foods in a reduced form, is present in dietary supplements and fortified foods in an oxidized synthetic form (folic acid). There is widespread agreement that maintaining adequate folate status is critical to prevent diseases due to folate inadequacy (e.g., anemia, birth defects, and cancer). However, there are concerns of potential adverse effects of excess folic acid intake and/or elevated folate status, with the original concern focused on exacerbation of clinical effects of vitamin B-12 deficiency and its role in neurocognitive health. More recently, animal and observational studies have suggested potential adverse effects on cancer risk, birth outcomes, and other diseases. Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations. Moreover, strong biological and mechanistic premises connecting elevated folic acid intake, UMFA, and/or high folate status to adverse health outcomes are lacking. However, the body of evidence on potential adverse health outcomes indicates the need for comprehensive research to clarify these issues and bridge knowledge gaps. Three key research questions encompass the additional research needed to establish whether high folic acid or total folate intake contributes to disease risk. 1) Does UMFA affect biological pathways leading to adverse health effects? 2) Does elevated folate status resulting from any form of folate intake affect vitamin B-12 function and its roles in sustaining health? 3) Does elevated folate intake, regardless of form, affect biological pathways leading to adverse health effects other than those linked to vitamin B-12 function? This article summarizes the proceedings of an August 2019 NIH expert workshop focused on addressing these research areas.

Deficiencies of folate or of vitamin B-12 are widespread and constitute a major global burden of morbidity that affect all age groups. Detecting or c

The risk of adverse effects of nitrous oxide (N₂O) exposure is insufficiently recognized despite its widespread use. These effects are mainly reported through case reports. We conducted an individual patient data meta-analysis to assess the prevalence of clinical, laboratory, and magnetic resonance findings in association with N₂O exposure in medical and recreational settings. We calculated the pooled estimates for the studied outcomes and assessed the potential bias related to population stratification using principal component analysis. Eighty-five publications met the inclusion criteria and reported on 100 patients with a median age of 27 years and 57% of recreational users. The most frequent outcomes were subacute combined degeneration (28%), myelopathy (26%), and generalized demyelinating polyneuropathy (23%). A T2 signal hyperintensity in the spinal cord was reported in 68% (57.2–78.8%) of patients. The most frequent clinical manifestations included paresthesia (80%; 72.0–88.0%), unsteady gait (58%; 48.2–67.8%), and weakness (43%; 33.1–52.9%). At least one hematological abnormality was retrieved in 71.7% (59.9–83.4%) of patients. Most patients had vitamin B12 deficiency: vitamin B12 15 µmol/L (90.3%; 79.3–100%), and methylmalonic acid >0.4 µmol/L (93.8%; 80.4–100%). Consistently, 85% of patients exhibited a possibly or probably deficient vitamin B12 status according to the cB12 scoring system. N₂O can produce severe outcomes, with neurological or hematological disorders in almost all published cases. More than half of them are reported in the setting of recreational use. The N₂O-related burden is dominated by vitamin B12 deficiency. This highlights the need to evaluate whether correcting B12 deficiency would prevent N₂O-related toxicity, particularly in countries with a high prevalence of B12 deficiency.