Cobalamin Deficiency in Children with Sickle Cell Disease
Authors: Hatabah Dunia , Kreiger Rachel , Brown Lou Ann , Harris Frank , Korman Rawan , Benedit Laura , Rees Chris A , Bakshi Nitya , Dampier Carlton , Morris Claudia R 
Published: June 2024

Abstract

Presentation Date: 6/9/2024
Presentation Start Time: 1:51:00 PM

Background
Cobalamin (B12)-deficiency has been reported in 18% of adults with sickle cell disease (SCD) vs 10% in adults without SCD. The prevalence of B12-deficiency in children with SCD is controversial with limited and contradictory data in the literature. A higher frequency of B12-deficiency in SCD is suspected due to higher rates of hemolysis, erythrocyte turnover, and increased nutritional requirements. B12 is an important cofactor for integral metabolic pathways involved in DNA synthesis, erythrocyte production and myelin production. B12-deficiency symptoms may vary from mild fatigue to clinically relevant neuropsychiatric symptoms to severe irreversible neurologic impairment. Diagnosis of B12-deficiency is challenging, as there is no gold standard. While measurement of serum B12 is known to be unreliable, it is commonly used as a screening tool, nevertheless. Methylmalonic acid (MMA) is a substrate of B12-dependent enzymatic reactions considered to be a more sensitive and specific marker of B12-deficiency and can be measured in either serum or urine. However, plasma MMA accumulates during renal dysfunction and may become inaccurate in the diagnosis of B12-deficiency in those with kidney impairment. While urine MMA/creatinine (MMA/Cr) ratio should account for renal disease, the impact of glomerular hyperfiltration defects common in SCD on both the renal clearance of MMA and its accumulation in the plasma is unknown. Therefore, the unique renal impairment of SCD may further complicate the reliability of both plasma and urine biomarkers of B12-deficiency. Currently no data exists to guide best practices for B12-deficiency screening in patients with SCD. Adding to the urgency of addressing B12-deficiency risk in this population is the increased use of nitrous oxide gas (N2O) in the United States particularly for dental procedures, and treatment of acute pain. Relevant to this study N2O is standard therapy for sickle-related vaso-occlusive-pain in France and Britain. Although N2O is generally considered safe, patients with B12-deficiency can experience serious neurologic complications, as it impacts cobalamin metabolism. Reports of neurologic sequalae in patients with SCD treated with N2O are emerging.

Objective
To evaluate the prevalence of B12-deficiency in children with SCD seeking care for pain in a pediatric emergency department (ED).

Methods
This is a secondary analysis of samples collected as part of ED-based clinical trials enrolling children with SCD and pain, evaluating mechanisms of hemolysis. Samples were part of a pharmacokinetics/pharmacodynamics and a phase II randomized control trial of IV arginine in children 3-21 years old with SCD hospitalized for pain receiving IV opioids. Blood and urine samples were analyzed from ED presentation before arginine therapy. B12-deficiency was defined as plasma MMA &gt;318 nmol/L or urine MMA/Cr ≥2.2 mmol/mol (based on Quest Diagnostics standard cut off values). Pearson’s correlation coefficient, Students t-test, and Pearson’s Chi-squared were used as appropriate. Percent agreement analysis was done between urine and plasma samples to assess for inter-rater reliability of B12-deficiency status.

Results
A total of 94 children (13±4 years, 54% female, 68% hemoglobin SS disease, and 72% on Hydroxyurea) were included. Fifty-two percent (49/94) had B12-deficiency diagnosed by either urine MMA/Cr, plasma MMA or both. Twenty-six percent (24/94) of patients were B12-deficient based on urine MMA/Cr, while 39% (37/94) were diagnosed by elevated plasma MMA. When comparing the urine and plasma data, there was agreement in deficient vs non- deficient status in 56/94 (60%) of the patients. Of all subjects found to be B12-deficient by either plasma or urine, 12 children (13%) were diagnosed with B12-deficiency identified in both plasma and urine. There were no significant differences in patient demographics or clinical characteristics in B12-deficient vs non-deficient groups. Plasma MMA and urine MMA/Cr did not correlate to any hematologic indices of B12-deficiency including hemoglobin and MCV.

Conclusions
Our data confirms that B12-deficiency is common in children with SCD with a concerning prevalence of 52% in our cohort. Given challenges with reliability of testing modalities currently available, it is not possible to determine whether this is an over- or under-estimation of the true prevalence of B12-deficiency in this population. Nonetheless, given the safety, affordability, and effectiveness of B12 supplementation (via injection or sublingual), alongside our current practice of administering folic acid to patients with SCD despite scarcity of evidence, it seems prudent to also consider incorporating B12 supplementation into our management regimen, to avoid detrimental consequences of an easily treatable cobalamin deficiency.