Beyond Macrocytosis: Unmasked Iron Deficiency Anemia in Autoimmune Gastritis

Background

Iron deficiency anemia (IDA) accounts for up to 50% of anemias globally (1), primarily resulting from blood loss, with less contribution from poor dietary intake, absorptive pathologies, and increased demand states. It leads to poor quality of life and increased healthcare expenditure, necessitating prompt diagnosis and treatment (2). Pernicious anemia (PA) is a vitamin B12 deficiency caused by autoimmune destruction of gastric parietal cells, leading to loss or dysfunction of intrinsic factor (3). While IDA coexists with and worsens outcomes in other anemias, less is known about its relationship with vitamin B12 deficiency in PA.

While Carmel et al. initially described a 20.7% prevalence of IDA in patients with PA (1), Lenti et al. later suggested that up to 20% of patients with unexplained or refractory IDA have pernicious anemia (4), pointing to a possible bidirectional relationship. The mechanisms of IDA in PA involve achlorhydria and its effects on iron absorption, Helicobacter pylori colonization in atrophic gastritis, and the regulation of erythropoiesis (4, 5). Given the burden of IDA in PA and the likelihood that PA treatment may unmask underlying IDA, we highlight the need for regular iron status assessment in PA patients (6).

Our case report details the diagnosis and initial care of a patient with serologically confirmed PA, in whom initial vitamin B12 replacement therapy is suspected to have unmasked a concurrent IDA, leading to interval recurrence and worsening of anemic symptoms. She was subsequently successfully evaluated for IDA and treated concurrently with vitamin B12 supplementation, achieving symptomatic resolution, highlighting the role of iron status assessment in PA patients.

Case Summary

Patient Information: A 42y.o. female, para 2+0, without medical comorbidities, was initially evaluated for a 6-month history of progressive bilateral lower-limb numbness, with accompanying tingling and a burning sensation on the plantar surfaces. She reported no lower-limb weakness, swelling, knee or low back pain at the time, and had no history of joint pain, constitutional symptoms, skin rash/lesions, hair loss, menstrual changes, Raynaud’s phenomenon, digital ulcers, dry eyes, neck swelling, altered bowel patterns, or dyspepsia. However, she reported occasional headaches 2 months prior to presentation, with lightheadedness, palpitations, and lethargy, but no syncope, convulsions, effort intolerance, cough, or leg swelling. There was no history of abnormal menstrual bleeding, gastrointestinal surgeries, prior liver disease, prolonged proton pump inhibitor use, inflammatory bowel disease, or worm infestations. She worked as a client relations officer and had no history of alcohol use, substance abuse, or chronic prescription medications.

Clinical Findings: Examination revealed a fair-appearing, well-dehydrated, afebrile patient without pallor or scleral icterus. Vital signs: blood pressure 130/79 mmHg, pulse 79 beats/min, oxygen saturation 97% on room air, temperature 36.90C, and respiratory rate 14 breaths/min. Her abdomen was nontender, of normal fullness, moving with respiration, with clear hernial orifices. Neurologically, her Glasgow Coma Scale (GCS) was 15/15, with grossly intact cognition and intellect. Pupils were bilaterally equal and reactive. No obvious cranial nerve palsies were noted, and power, bulk, and tone were normal in both limbs. Clonus and Babinski were negative bilaterally, but fine touch assessment was equivocal. Bilateral +1 ankle reflexes were noted, with preserved knee reflexes. Coordination and proprioception were normal, as were cardiovascular and respiratory system assessments.

Diagnostic Assessment: Per Table 1 below, she had macrocytic anemia, low vitamin B12 levels, negative antiparietal cell antibodies (APCA), positive intrinsic factor antibodies (IFA), and elevated serum homocysteine at 23.8 umol/ml (5-15). Her erythrocyte sedimentation rate (ESR) was normal at 7 mm/hr (0-20), as were thyroid-stimulating hormone (TSH) 1.57 mIU/l (0.3-3.94), calcium 2.14 mmol/l (2.10-2.60), magnesium 0.81 mmol/l (0.7-0.9), and folate 33.95 ng/ml (7.2-34.8). She had a negative Helicobacter pylori antigen test, low vitamin D3 28.64 ng/ml (30-50), and a negative rapid plasma reagin (RPR). Her urea, electrolytes, and creatinine (UECs), urinalysis, liver function tests (LFTs), hemoglobin A1C (5.4%), antinuclear antibodies (ANA), lipid panel, basic toxicology, and virology panel were normal. Nerve conduction studies (NCS) were not performed due to cost and availability. An assessment of distal symmetric chronic sensory neuropathy with macrocytic anemia due to vitamin B12 deficiency was made.

Therapeutic Intervention: She was apprised of the chronic nature of her condition and the need for lifelong replacement therapy, and was initiated on a daily vitamin B12 nasal spray. She was also given a 3-month prescription for pregabalin 75 mg nightly and vitamin D supplementation (600 IU/day). At her 3-month review, her neuropathy had substantially resolved, and she could now sleep better and concentrate on her office tasks. Her repeat vitamin B12 level was 222 ng/mL and continued to rise, reaching a 12-month peak of 707 ng/mL (Figure 1). However, she subsequently stopped using the spray 3 months before her scheduled 18-month review, owing to concerns about ‘nasal discomfort’ felt each time she used it, and to new-onset malaise, palpitations, and difficulty concentrating at work, which she described as odd and not in tandem with her previous symptoms. The neuropathy, however, did not recur.

Further care and follow-up: At her 18-month review, her vitamin D3 level was 42.16 ng/mL, and the repeat vitamin B12 level was 90 ng/mL. Other electrolytes and the metabolic panel were normal. Her CBC, however, was now microcytic, with hemoglobin 11.5 g/dL (12-16.5), red cell volume 73 fL (83-101), platelet count 251 × 10^3/µL (150-410), and white cell count 6.19 × 10^6/µL (4-10). A concomitant iron deficiency was suspected to have been unmasked by the initial B12 treatment, accompanied by a now-relapsing B12 deficiency. Thus, confirmatory iron studies revealed a serum iron level of 4.51 µmol/L (5.83-34.5), transferrin 2.99 g/L (2.50-3.80), transferrin saturation 6.0% (20-50%), and ferritin 6.31 ng/mL (13-150). An esophagogastroduodenoscopy (EGD) follow-up after positive occult stool testing showed mild gastritis (Figure 2), and biopsy findings showed chronic pylori-negative gastritis without glandular atrophy, dysplasia, or intestinal metaplasia. Colonoscopy was normal.

She was initiated on IV ferric carboxymaltose on alternate days for 3 doses. Repeat ferritin level 1 month later was 134 ng/mL, with complete resolution of her fatigue. Additionally, Stherapy for vitamin B12 deficiency was commenced almost simultaneously, initially with intramuscular hydroxocobalamin 1000 mcg every other day for 2 weeks, then quarterly for life. Subsequent reviews have shown no concerns. B12 level 1 month post re-initiation was 309 ng/mL, with hemoglobin 12.9 g/dL (12-16.5), red cell volume 82.4 fL (83-101), platelet count 156 × 10^3/µL (150-410), and white cell count 4.19 × 10^6/µL (4-10).

Discussion

Vitamin B12 deficiency and PA are hallmarks of autoimmune gastritis (AIG). In this case, the initial diagnosis of PA was based on anemic symptoms (lethargy, palpitations, and effort intolerance), low B12 levels, elevated serum homocysteine, and a positive IFA, and treatment was appropriately initiated. However, initial improvement followed by interval worsening of the patient's status and the development of microcytosis necessitated re-evaluation of the coexistence of IDA and PA. Notably, while B12 deficiency has long been established as the major consequence of AIG, achlorhydria and intrinsic factor loss or dysfunction also cause iron and other micronutrient malabsorption (6). Consequently, iron and other micronutrient deficiencies may ensue, necessitating a broader assessment and care.

Characteristically, IDA may be diagnosed before or during the initial PA diagnosis in about 20%-52% of cases, or within the first fourteen months of PA diagnosis in 23%-46.4% of patients (1, 3). Rogez et al., in their PA cohort study, reported iron deficiency in 46.4% of newly diagnosed PA patients and in 28.3% during follow-up (6). This emergence of concurrent or unmasked IDA in PA patients is hypothesized to be linked to AIG disease duration, severity, and molecular dynamics that influence disease evolution (7).

An initial concurrent diagnosis often points to longstanding PA with established malabsorptive effects, and microcytosis from IDA or normocytosis can mask and delay the diagnosis of B12 deficiency (5). Iron deficiency in this segment results from reduced iron absorption due to longstanding achlorhydria from gastric parietal gland atrophy (5). Thus, hypothetically, vitamin B12 replacement before correction of IDA could further worsen iron deficiency (7).

In later diagnosis, also called unmasked iron deficiency, as in our case, IDA development is thought to be a consequence of improved erythropoiesis after vitamin B12 supplementation (2). Here, renewed erythropoiesis consumes the already meager iron stores, causing a further decline in iron levels and leading to symptomatic IDA.

IDA treatment involves iron supplementation. The choice between oral and intravenous iron formulations depends on availability, tolerability, cost, and comorbidities (8). In our case, the oral formulation was avoided because of dyspeptic concerns, impaired absorption, and the need to rapidly correct the anemia. IV iron has been shown to increase hemoglobin, serum iron, and ferritin levels more than oral iron, but it does not reduce the need for transfusion (8, 9).

Conclusion

In summary, our case report affirms that IDA should be suspected and actively evaluated in all patients with PA. The assessment should include routine iron tests (serum iron, ferritin, and transferrin saturation), and alternative causes of IDA should be excluded. Notably, treatment should be initiated concurrently with B12 replacement therapy for symptomatic resolution.

Source of Funding

No funding was used for this research.

Availability of Data

The patient data used in advancing the case review can be requested from the authors.

Conflict of Interest

The authors declare no conflict of interest.