Combination of Vitamin B₁₂-Deficiency Anemia and Autoimmune Hemolytic Anemia: Is the Diagnosis Always Straightforward?

ABSTRACT. This article presents a clinical observation illustrating the differential diagnosis between the true combination of B12-deficiency pernicious anemia (PA) and autoimmune hemolytic anemia and the phenomenon of “pseudo-hemolysis.” A 71-year-old female patient with verified PA against a background of autoimmune atrophic gastritis and concomitant autoimmune thyroiditis was found to have macrocytic anemia, hyperbilirubinemia, elevated lactate dehydrogenase (LDH), and a positive direct Coombs test (DAT) with negative anti-erythrocyte antibodies. The key criterion was the reticulocyte production index (RPI = 1.38), indicating ineffective erythropoiesis characteristic of PA rather than true hemolysis. Cyanocobalamin monotherapy caused a reticulocyte crisis, decreased LDH and bilirubin, and increased hemoglobin, confirming the false-positive nature of the DAT. The authors conclude that a positive Coombs test in PA does not require the administration of glucocorticosteroids; correct interpretation allows avoiding unnecessary immunosuppression.

For citation: Belousova EN, Kosterina AV, Shashina MS, Sadykova LR. Combination of vitamin B₁₂-deficiency anemia and autoimmune hemolytic anemia: Is the diagnosis always straightforward? Therapy (Moscow). 2026;12(5S):138–142.
https://doi.org/10.18565/therapy.2026.5-s5.138-142

INTRODUCTION

Pernicious anemia (PA) is a form of vitamin B₁₂ deficiency anemia that develops in the setting of autoimmune atrophic gastritis. In this condition, vitamin B₁₂ is not absorbed because of intrinsic factor deficiency, resulting in megaloblastic hematopoiesis with ineffective erythropoiesis [1, 2]. PA is frequently associated with other autoimmune diseases, including autoimmune thyroiditis, vitiligo, and type 1 diabetes mellitus [3].

PA is diagnosed in the presence of macrocytic anemia with a low reticulocyte count, a low serum vitamin B₁₂ level, and laboratory and endoscopic confirmation of autoimmune atrophic gastritis (positive antibodies to gastric parietal cells and/or intrinsic factor and findings from esophagogastroduodenoscopy (EGD) with biopsy) [4].

The phenomenon of “pseudo-hemolysis” in vitamin B₁₂ deficiency anemia, which occurs in approximately 85% of cases, poses a diagnostic challenge [5]. High lactate dehydrogenase (LDH) activity, elevated indirect bilirubin, and reduced haptoglobin are common laboratory findings in PA and result from intramedullary destruction of megaloblasts rather than true hemolysis in the peripheral blood [6, 7]. In some cases, these abnormalities are accompanied by a positive direct antiglobulin test (DAT), creating the impression of autoimmune hemolytic anemia (AIHA) and necessitating differential diagnosis.

A positive DAT in PA has been described in the literature as a rare phenomenon. It is essential to distinguish this situation from true concomitant PA and AIHA, which has also been reported in isolated cases [8, 9]. In the former situation, treatment is limited to vitamin B₁₂ replacement, whereas the latter requires the addition of glucocorticoids or other immunosuppressive therapy.

Calculation of the reticulocyte production index (RPI) is a key differential diagnostic tool for distinguishing ineffective erythropoiesis in PA from true immune-mediated hemolysis [10].

We present a clinical case illustrating the diagnostic algorithm for macrocytosis, signs of hemolysis, and a positive DAT.

CASE PRESENTATION

A 71-year-old woman (Patient V.) was admitted in November 2025 to the Republican Clinical Hospital (Republic of Tatarstan) with exertional dyspnea, marked generalized weakness, dry mouth, painful oral ulcers, a metallic taste, a 3–4 kg weight loss over 4 months, loss of appetite, and decreased sensation in the lower extremities.

According to her medical history, in 2017, Patient V. consulted a gastroenterologist because of epigastric pain. Esophagogastroduodenoscopy (EGD) revealed gastric polyps, and polypectomy was performed. Her erythrocyte sedimentation rate (ESR) was 60 mm/h.

In October 2024, the patient sought medical attention because of generalized weakness, epigastric pain, and altered taste. A complete blood count (CBC) revealed macrocytic anemia (hemoglobin, 80 g/L; mean corpuscular volume (MCV), 121 fL), and the ESR was 60 mm/h. Blood chemistry showed an elevated total bilirubin level of 65 μmol/L, with a direct bilirubin level of 6.2 μmol/L; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were within the reference ranges. EGD with biopsy revealed signs of atrophic gastritis. Gastric parietal cell antibodies were detected at a high titer of 1:1280, and the anti-intrinsic factor antibody level was 59.6 U/L (reference range, 0–6 U/L). Because of progressive weakness, the patient was hospitalized for further diagnostic evaluation.

Her medical history included autoimmune thyroiditis, with euthyroidism maintained on levothyroxine 75 μg, post-tuberculous pulmonary fibrosis, and generalized atherosclerosis, for which she was receiving rosuvastatin 10 mg. Vitamin B₁₂-deficiency anemia was reported on the maternal side of the family. Patient V. denied smoking or alcohol use.

On physical examination, her general condition was satisfactory, and she was alert. She had a hypersthenic body habitus, weighed 85 kg, and was 156 cm tall. Her body mass index was 34.9 kg/m², corresponding to class I obesity. The skin and visible mucous membranes were icteric and free of lesions. The sclerae were also icteric. Examination of the oral cavity revealed a smooth tongue with flattened papillae and no coating. The peripheral lymph nodes were not enlarged and were nontender. The thyroid gland was not palpable. No peripheral edema was pre...

E.N. Belousova, A.V. Kosterina, M.S. Shashina, L.R. Sadykova