Metformin is a cornerstone therapy for type 2 diabetes mellitus due to its glucose-lowering efficacy and additional benefits such as reducing cardiovascular mortality. However, accumulating evidence suggests an association between long-term metformin use and vitamin B12 deficiency, which can lead to serious clinical consequences. This review aims to synthesize current knowledge on the pathogenesis, prevalence, clinical implications, and management of metformin-induced vitamin B12 deficiency. Given the significant clinical implications, it is crucial to monitor and manage vitamin B12 levels in patients using metformin. This review emphasizes the importance of early detection and supplementation to prevent adverse outcomes. By analyzing the current evidence, the review aims to inform healthcare professionals about best practices for managing vitamin B12 deficiency in patients on metformin, offering insights to guide future clinical practices and research directions.

Nitrous oxide (N2O) has been thought to be a harmless recreational substance by public perception, but it has been linked to subacute combined degeneration (SACD) due to induction of a functional vitamin B12 deficiency via oxidation and inactivation of the cobalt ion in its molecular structure. N2O has been rising in popularity due to several factors including accessibility, low cost, and low perceived risk, leading otherwise healthy people to develop what used to be a neurological disease experienced by select patient populations with dietary restrictions or medical conditions leading to low levels of vitamin B12. Vitamin B12 plays a crucial role in many cellular processes, and loss of functional vitamin B12 cannot be detected by measuring it directly. Substrates from its metabolic pathways such as homocysteine and methylmalonic acid must be measured to check its functional status. Vitamin B12 deficiency also leads to a hypercoagulable state due to the build-up of homocysteine in the blood. We present the case of a 26-year-old male who had reportedly used N2O for six months leading to SACD and a popliteal deep vein thrombosis. The options for treatment are abstaining from substance use and vitamin B12 supplementation; however, full recovery after SACD develops is unlikely and patients may be left with permanent neurological dysfunction from N2O use.

Pancytopenia is a complex medical condition characterized by decreased levels of red blood cells (RBCs), white blood cells (WBCs), and platelets (PLTs). It can arise from impaired production, peripheral destruction, or a combination of both. The causes of pancytopenia range from reversible factors like infections and medication reactions to irreversible conditions. Vitamin B12 deficiency is a notable reversible cause that can take years to manifest in adults due to stored reserves. However, deficiencies caused by impaired absorption, especially due to the lack of intrinsic factors (IFs), can lead to rapid deterioration within two to five years. A healthy 39-year-old male with an athletic lifestyle presented with symptoms such as dizziness, nausea, vomiting, palpitations, and fainting over a few days. These symptoms were preceded by weeks of persistent body aches, headaches, weakness, daily fevers, chills, and night sweats. Vital signs were stable. The physical examination revealed conjunctival pallor and lymphadenopathy in the submandibular and superficial cervical regions. Initial blood tests showed normocytic anemia (Hgb 4.9, MCV 80), leukopenia (2.99), thrombocytopenia (142), and elevated liver enzymes (AST 199, ALT 96, and total bilirubin of 2.04). The peripheral smear showed tear-drop cells and hypochromic cells. The initial impression was hematologic malignancy, including but not limited to leukemia, lymphoma, or myelofibrosis given clinical findings such as B-symptoms like night sweats, neck lymphadenopathy, and subjective daily fever, along with pancytopenia. The patient received a bolus of normal saline and a transfusion of two units of packed RBCs. CT scans of the chest, abdomen, and pelvis showed no adenopathy or splenomegaly. Although initial clinical assessment pointed toward a potential hematologic malignancy, comprehensive testing, including SPEP, reticulocyte count/fraction, serum folate, and serum vitamin B12, revealed only severe vitamin B12 deficiency, with a level of less than 150, with the presence of IF antibodies. Treatment involved intensive in-patient vitamin B12 injections followed by a detailed outpatient regimen. The patient completed a daily dose of vitamin B12 injections for seven consecutive days, followed by weekly injections for the next four weeks. Subsequent laboratory results demonstrated an increase in WBC count to 8.39, Hgb level to 13.2, and PLT count of 249, indicating a continued positive response to the vitamin B12 replacement therapy. In summary, pancytopenia poses a diagnostic challenge that demands careful evaluation of patient data and comprehensive testing. Vitamin B12 deficiency, which encompasses pernicious anemia (PA), is among the reversible factors to consider. This aspect holds significance before opting for more invasive measures like a bone marrow biopsy. Nutritional deficiencies need to be considered first as differentials in pancytopenia, even in the absence of typical signs of vitamin B12 deficiency (like macrocytosis and hypersegmented neutrophils) and in the presence of compelling clinical indications pointing to a hematologic malignancy.

The case report by Dwyre et al. shows that vitamin B12 deficiency may be misdiagnosed as acute thrombotic thrombocytopenic purpura. Together with similar observations, this underlines that acquired vitamin B12 deficiency-besides the inherited disorder of intracellular cobalamin metabolism, cbl C disease-should be listed as a separate entity of the thrombotic microangiopathies. Commentary on: Dwyre et al. Microangiopathic thrombocytopenia caused by vitamin B12 deficiency responding to plasma exchange. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19625.

Methotrexate (MTX), a commonly used disease-modifying antirheumatic drug, is generally considered safe at low cumulative doses. However, severe pancytopenia can occur even with doses as low as 10 mg, as illustrated by a fatal case in an older adult with chronic kidney disease (CKI) and vitamin B12 deficiency. Despite the low dose and lack of folate supplementation, the patient developed severe mucositis and pancytopenia leading to fatal complications. This case underscores the challenges in diagnosing and managing MTX-induced pancytopenia, especially in patients with comorbidities such as CKI and vitamin B12 deficiency.

Vitamin B12 (cyanocobalamin) deficiency can lead to ineffective erythropoiesis, intramedullary hemolysis, and, in severe cases, neurologic deficits. Some of those findings are also features of thrombotic microangiopathies, specifically thrombotic thrombocytopenic purpura (TTP), and the distinction between both entities could sometimes be challenging. While the treatment of the former consists of enteral or parenteral repletion, the treatment of TTP is more complex and time-sensitive. For that reason, refining diagnostic strategies is crucial to avoid misdiagnosis and unnecessary interventions. Here is an example of a potential life-threatening hemolysis caused by vitamin B12 deficiency with acute onset neurologic symptoms, which resolved with B12 repletion.

Metformin is the most widely used antihyperglycemic drug in patients with type 2 diabetes (T2D). Over the past 2 decades, several studies have highlighted a substantial increase in the risk of vitamin B12 deficiency in patients with T2D on metformin therapy. This can lead to several complications and induce or exacerbate peripheral neuropathy. Despite these data, there are no definite guidelines for screening, diagnosing, and treating vitamin B12 deficiency in patients with T2D on metformin therapy. Therefore, in this narrative review, we aimed to suggest a practical diagnostic and therapeutic strategy to address vitamin B12 deficiency in patients with T2D receiving metformin treatment. Clinical evidence supporting an increased risk of vitamin B12 deficiency in patients with T2D on metformin therapy and its risk factors and potential complications are also discussed.

Pernicious anemia, stemming from Vitamin B12 deficiency and autoimmune processes affecting intrinsic factor production, presents challenges in early diagnosis due to vague initial symptoms. This case report introduces a unique occurrence of pernicious anemia-induced peripheral neuropathy in a patient with concurrent HLA-B27 arthropathy, highlighting the complex interplay of autoimmune mechanisms. While HLA-B27 is not typically associated with pernicious anemia, the case underscores the importance of exploring specific HLA haplotypes in understanding the nuanced manifestation of autoimmune disorders. Comprehensive screening for anti-intrinsic factor and anti-parietal cell antibodies is crucial in individuals with signs of pernicious anemia, especially those with a history of HLA-B27 arthropathy, guiding tailored management strategies. This report contributes to the ongoing exploration of the intricate autoimmune landscape in pernicious anemia.

Optic neuritis is a rare presentation of vitamin B12 deficiency. We describe a 33-year-old female patient living with HIV presenting with progressive loss of vision for 1 week. She had a history of severe peripheral neuropathy that was managed with vitamin B12-containing tablets approximately three years before presenting with progressive loss of vision. On examination, she had no perception of light in the left eye and no perception of hand motion in the right eye. The fundus in her left eye had mild blurring of disc margins. Results from tests done showed a haemoglobin of 12.9g/dl, MCV 101fl, a serum vitamin B12 of 78pmol/l, and cytomegalovirus (CMV) test showed no active disease. She was diagnosed with optic neuritis and started on 30 mg tablets of prednisolone for 1 week with slight improvement. She was then started on vitamin B12 injections 1 mg daily for 10 days and thereafter, monthly for 6 months. She reported gradual improvement and regained her sight after 5 months treatment of with Vitamin B12 injections. Ophthalmic manifestations of vitamin B12 deficiency are not common and may present without haematological signs therefore, a high index of suspicion is required for early diagnosis and management of vitamin B12 deficiency.

A young adult African American female presented with normocytic microangiopathic haemolytic anaemia, elevated lactate dehydrogenase and thrombocytopenia. The patient responded to therapeutic plasma exchanges (TPE) for presumed thrombotic microangiopathy caused by thrombotic thrombocytopenic purpura (TTP). After relapsing, the patient was found to have pancytopenia, megaloblastic bone marrow and low vitamin B12 consistent with pernicious anaemia, which improved with intramuscular B12 and discontinuation of TPE. B12-deficient macrocytosis was not seen at presentation due to concomitant alpha-thalassaemia. Initial clinical/laboratory improvement is attributed to B12 present in TPE plasma. B12 deficiency can mimic TTP. Vigilance is needed regarding atypical presentations of pernicious anaemia.