Vitamin B12 Deficiency in Sickle Cell Disease: Method-Driven Estimates and Systematic Diagnostic Misclassification

Area of Science:

• Hematology
• Nutritional Biochemistry
• Clinical Diagnostics

Background:

• The reported prevalence of vitamin B12 deficiency in sickle cell disease (SCD) ranges significantly from 0% to 70%.
• This wide variation may stem from differences in diagnostic methodologies rather than genuine population-level variations.
• Accurate assessment of vitamin B12 status is crucial for managing SCD complications.

Purpose of the Study:

• To critically evaluate the diagnostic methods used to assess vitamin B12 status in individuals with SCD.
• To determine if reported prevalence estimates reflect true biological variation or are influenced by diagnostic misclassification.
• To assess the impact of different diagnostic strategies on prevalence estimates in SCD.

Main Methods:

• A systematic review adhering to PRISMA 2020 guidelines was conducted.
• Searches were performed on PubMed, AJOL, and Google Scholar, including citation tracking and dual screening of observational studies from 2000 to 2026.
• A novel framework was used to assess diagnostic validity, considering biomarker strategy, analytical platforms, thresholds, and confounder control.

Main Results:

• Fourteen studies were included, with 57% from high-income countries and 43% from low- and middle-income countries (LMIC).
• Diagnostic approaches were often limited, with 71% using immunoassays and over a third relying solely on circulating vitamin B12 levels.
• Prevalence estimates varied significantly (0%-70% in single-marker studies, 6.9%-53% in multi-marker studies), strongly influenced by the diagnostic methods employed, with greater discordance observed in LMIC settings.

Conclusions:

• Current diagnostic methods for vitamin B12 in SCD are highly dependent on the specific assay and approach used.
• The heterogeneity in prevalence estimates suggests uncertain clinical validity and challenges existing data.
• Findings necessitate revised clinical practices, research designs, and a focus on diagnostic equity for vitamin B12 assessment in SCD.