Patient-reported symptom profiles in vitamin B12 deficiency and pernicious anaemia: A cross-sectional study using latent class analysis

Pernicious anemia is a chronic autoimmune disease characterized by impaired of vitamin B12 absorption and deficiency. Current diagnostic approaches rely on laboratory biomarkers with limitations in sensitivity and specificity, leading to diagnostic uncertainty and potentially delayed and/or suboptimal treatment. The 2024 NICE guidelines acknowledge that treatment frequency should be guided by individual symptom response rather than current one-size-fits-all schedules; however, the symptom heterogeneity underpinning this recommendation remains poorly characterized. We conducted secondary analysis of symptom survey data from 1,117 members of the Pernicious Anaemia Society (PAS) collected between August 2010 and November 2012. We applied latent class analysis (LCA) to 46 self-reported indicators comprising demographic characteristics, symptoms, and comorbid conditions, to identify distinct symptom-based subtypes and assess whether such subgroups can inform more tailored management of PA. Associations between symptom subtypes and diagnostic test results, age when symptoms first started, symptom duration, and treatment satisfaction were examined using chi-square and Fisher's exact tests. The best model included three distinct symptom subtypes: High Burden (n=334, 29.9%), Moderate Burden (n=613, 54.9%), and Low Burden (n=170, 15.2%). The High Burden subtype exhibited fatigue (99.4%), cognitive dysfunction (97.9% memory loss), neurological manifestations (95.5% clumsiness), and suicidal thoughts (41.6%). Intrinsic factor antibody (IFA) status did not differ significantly across subtypes ({chi}2=1.04, df=2, p=0.593). Age at symptom onset differed significantly across subtypes (p=0.002), with the Low Burden subtype overrepresented in older age groups. The High Burden subtype had the longest diagnostic delays (56.9% >2 years). Standard three-monthly injections showed low satisfaction across all classes (High Burden: 8.5%, Moderate Burden: 23.7%, Low Burden: 30.7%). Symptom-based stratification identifies clinically meaningful subgroups independent of IFA status, supporting tailored, symptom-guided treatment rather than the current piecemeal approach. The inverse association between high symptom burden and age of onset warrants clinical attention. The co-occurrence of markedly elevated rates of depression and suicidal thoughts in the High Burden subtype suggest that integrated mental health assessments should form part of routine clinical management.