Excess Folic Acid and Vitamin B12 Deficiency: Clinical Implications?

BACKGROUND: In the 1940s to 1950s, high-dose folic acid supplements (>5 mg/d) were used clinically to reverse the megaloblastic anemia of vitamin B12 deficiency caused by pernicious anemia. However, this treatment strategy masked the underlying B12 deficiency and possibly exacerbated its neuropathological progression. The issue of masking and exacerbating B12 deficiency has recently been rekindled with the institution of folic acid fortification and the wide-spread use of folic acid supplements. OBJECTIVES: The objectives of this review are to describe clinical and epidemiological evidence that excess folic acid exacerbates B12 deficiency, to summarize a hypothesis to explain this phenomenon, and to provide guidance for clinicians. RESULTS: Cognitive function test scores are lower and blood homocysteine and methylmalonic acid concentrations are higher in people with low B12 and elevated folate than in those with low B12 and nonelevated folate. High-dose folic acid supplementation in patients with pernicious anemia or epilepsy cause significant reductions in serum B12. It is hypothesized that high-dose folic acid supplements cause depletion of serum holotranscobalamin and thus exacerbate B12 deficiency. CONCLUSION: The evidence for excess folic acid exacerbating B12 deficiency is primarily correlative or from uncontrolled clinical observations, and the hypothesis to explain the phenomenon has not yet been tested. Nonetheless, the evidence is sufficiently compelling to warrant increased vigilance for identifying B12 deficiency in at risk individuals, including older adults and others with low B12 intake or conditions that are associated with B12 malabsorption, who also ingest excessive folic acid or are prescribed folic acid in high doses.

Plain language titleExcess Folic Acid and Vitamin B12 Deficiency: Clinical Implications?Plain language summaryIt has been known for many decades that high doses of the B vitamin supplement, folic acid, can alleviate the anemia of vitamin B12 deficiency, at least temporarily. However, by alleviating the anemia, such folic acid supplements were said to "mask" the underlying vitamin B12 deficiency, thus allowing neurological damage to continue or possibly be exacerbated. Consequently, treating vitamin B12 deficiency with high dose folic acid was discontinued in the 1970s. The issue of whether folic acid supplements can exacerbate vitamin B12 deficiency reemerged in the 1990s with folic acid fortification of cereals and grains in the United States and Canada (and now in over 80 countries around the world) to prevent spina bifida and other birth defects. This narrative review summarizes the results of studies that have assessed the relationships between folic acid and folate and vitamin B12 status in patients and in populations. A recent hypothesis on how folic acid might exacerbate vitamin B12 deficiency is summarized, and recommendations to clinicians are made for increased vigilance in assessing vitamin B12 status in certain groups at risk of vitamin B12 deficiency, including older adults, people with gastrointestinal issues and other factors that cause vitamin B12 malabsorption, people with unexplained neurological problems, and people who follow vegan or vegetarian diets which are naturally low in vitamin B12.

Oral vitamin B12 supplementation in pernicious anemia: a prospective cohort study.

BACKGROUND: The absorption of vitamin B12 is hindered in pernicious anemia (PA) owing to intrinsic factor deficiency. Traditionally, intramuscular vitamin B12 injections were the standard treatment, bypassing the impaired absorption. Although there is potential for oral vitamin B12 supplementation through passive enteral absorption, it is not commonly prescribed in PA owing to limited studies assessing its efficacy. OBJECTIVES: We aimed to assess the efficacy of oral vitamin B12 supplementation in PA. METHODS: We enrolled participants diagnosed with incident vitamin B12 deficiency related to PA. The diagnosis of PA was based on the presence of classical immune gastritis and of anti-intrinsic factor and/or antiparietal cell antibodies. To evaluate the vitamin B12 status, we measured total plasma vitamin B12, plasma homocysteine, and plasma methylmalonic acid (pMMA) concentration and urinary methylmalonic acid-to-creatinine ratio. Participants were treated with oral cyanocobalamin at a dosage of 1000 µg/d throughout the study duration. Clinical and biological vitamin B12 deficiency related features were prospectively and systematically assessed over the 1-y study duration. RESULTS: We included 26 patients with vitamin B12 deficiency revealing PA. Following 1 mo of oral vitamin B12 supplementation, 88.5% of patients were no longer deficient in vitamin B12, with significant improvement of plasma vitamin B12 [407 (297-485) compared with 148 (116-213) pmol/L; P < 0.0001], plasma homocysteine [13.5 (10.9-29.8) compared with 18.6 (13.7-46.8) µmol/L; P < 0.0001], and pMMA [0.24 (0.16-0.38) compared with 0.56 (0.28-1.09) pmol/L; P < 0.0001] concentrations than those at baseline. The enhancement of these biological parameters persisted throughout the 12-month follow-up, with no patients showing vitamin B12 deficiency by the end of the follow-up period. The median time to reverse initial vitamin B12 deficiency abnormalities ranged from 1 mo for hemolysis to 4 mo for mucosal symptoms. CONCLUSIONS: Oral supplementation with 1000 µg/d of cyanocobalamin has been shown to improve vitamin B12 deficiency in PA.

Iron deficiency in pernicious anemia: Specific features of iron deficient patients and preliminary data on response to iron supplementation.

BACKGROUND & AIMS: While vitamin B12 (B12) deficiency is considered as the hallmark of pernicious anemia (PA), iron deficiency (ID) is also prevalent. Indeed, this auto immune gastritis is responsible for parietal cell atrophy and increase in gastric pH, leading to impaired iron absorption. We compared PA patients' features according to their iron status at PA diagnosis, and we assessed the iron status recovery after oral or intravenous iron supplementation. METHODS: We prospectively included patients presenting with a newly diagnosed PA in a tertiary referral hospital between November 2018 and October 2020. Iron status was assessed at PA diagnosis then regularly during a standardized follow-up. In case of ID, the decision of treatment with oral and/or intravenous iron supplementation was left to the clinician convenience. RESULTS: We included 28 patients with newly diagnosed PA. ID was observed in 21/28 (75.0%) patients: from the PA diagnosis in 13 patients, or during the follow-up in 8 patients. Iron deficient PA patients had higher plasma B12 (p = 0.04) and lower homocysteine levels (p = 0.04). Also, ID was independently associated with the 'APCA (anti-parietal cell antibodies) alone' immunological status (absence of anti-intrinsic factor antibodies) after adjustment for age, gender and B12 level (aOR 12.1 [1.1-141.8], p = 0.04). High level of APCA was associated with lower ferritin level. After 3 months of supplementation, 3/11 PA patients normalized the iron status with oral iron supplementation, versus 7/8 with intravenous iron supplementation (p = 0.02). CONCLUSION: The high frequency of iron deficiency in PA highlights the interest of regular assessment of iron status in this condition. ID was associated with a profile including APCA alone and less pronounced B12 deficiency. Intravenous iron supplementation seemed to be more efficient than an oral supplementation in these preliminary data.

A New Case of Association of Megaloblastic Anemia and Pancytopenia of Infants.

BACKGROUND: Vitamin B12, or cobalamin deficiency, an infrequent clinical entity in pediatric age, is found almost solely in breastfed infants whose mothers are purely vegetarian, non-supplemented or with pernicious anemia. Megaloblastic anemia in infants presents with generalized weakness or irritability. METHODS: Diagnosis is usually centered on complete blood count, vitamin dosing, and peripheral smear, which may show macrocytes, hypersegmented neutrophils, reticulocytopenia and a raised mean corpuscular volume (MCV ˃ 100 fL). Pancytopenia has also been noted. RESULTS: We report an exclusive breastfed nine-month-old female child who presented with irritability, developmental delay, and difficulties in introducing new foods. Her initial blood count revealed pancytopenia. Vitamin B12 levels were found to be reduced. Maternal levels of Vitamin B12 were also found to be borderline low. The child was treated as per protocols, and improvement was evidenced with the return of hematological parameters to the regular and gradual advancement of milestones. CONCLUSIONS: We aim to underscore the importance of megaloblastic anemia as an important and rare cause of anemia in infancy.

A case report: subacute combined degeneration of the spinal cord and pernicious anemia caused by autoimmune gastritis.

INTRODUCTION: Autoimmune gastritis causing both subacute combined degeneration of the spinal cord and pernicious anemia is rare in clinical practice. Here, we report a case of subacute combined degeneration of the spinal cord and pernicious anemia resulting from vitamin B12 deficiency due to autoimmune gastritis. PATIENT CONCERNS: A 66-year-old woman presented with a 2-month history of numbness in her extremities. DIAGNOSES: The diagnoses were (1) autoimmune gastritis (2) subacute combined degeneration of the spinal cord (3) pernicious anemia (4) hypergastrinemia (5) chronic lymphocytic thyroiditis. INTERVENTIONS: The patient received intramuscular methylcobalamin treatment for 5 days, followed by oral methylcobalamin daily.Outcomes: Symptoms improved, and anemia recovered in the second month after discharge. She discontinued her medication afterward, and the neurological symptoms recurred. CONCLUSIONS: Autoimmune gastritis can lead to several diseases if not intervened in the early course. Neuropathy and hematopathy recur with treatment discontinuity. Methylcobalamin and adenosylcobalamin are unlikely to be more effective than vitamin B12.

Pernicious anaemia: cause of recurrent cerebral venous thrombosis.

This case of recurrent cerebral venous thrombosis (CVT) highlights hyperhomocysteinemia in pernicious anemia due to vitamin B12 deficiency. No other risk factors such as trauma, infections, coagulation disorders or autoimmune diseases were present. The patient was cured with vitamin B12 and anticoagulation therapy. So, it is worthwhile and important to investigate levels of vitamin B12 and homocysteine in CVT.

Máculas eritematosas urentes orales como manifestación inicial de deficiencia de la vitamina B12 / Burning Erythematous Oral Macules as the Presenting Manifestation of Vitamin B12 Deficiency

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Subacute combined degeneration: a case of pernicious anaemia without haematological manifestations.

Vitamin B12 deficiency can be caused by a diverse group of aetiologies. One of the less common of these is an autoimmune condition pernicious anaemia, so named after the most common physiological manifestation of B12 deficiency: anaemia. However, B12 is also necessary for nervous system function and its depletion can lead to dysfunction of the posterior columns of the spinal cord resulting in subacute combined degeneration (SCD). This disease, while debilitating in its acute phase, can usually be mostly if not fully reversed if caught early and treated appropriately. Early detection can prove challenging if there are no haematological manifestations of B12 deficiency and the only guidance is the high index of suspicion. We present a case of pernicious anaemia leading to SCD without any clinical or laboratory findings of anaemia in this report.

Toxicity induced by multiple high doses of vitamin B12 during pernicious anemia treatment: a case report.

Context: The clinical consequences of excess vitamin B12 induced by multiple oral doses of cyanocobalamin are not well-known.Case details: A young woman was treated with multiple daily doses of 1 mg of cyanocobalamin for severe pernicious anemia. After a total dose of 12 mg, she developed acne, palpitations, anxiety, akathisia, facial ruddiness, headache, and insomnia. She improved two weeks after stopping the drug. There were no sequelae nor complications.Discussion: Although these symptoms of cobalamin toxicity were unexpected and unusual, the case reminds us that the administration of any drug is not entirely safe.

Nutritional neuropathies.

Neuropathies associated with nutritional deficiencies are routinely encountered by the practicing neurologist. Although these neuropathies assume different patterns, most are length-dependent, sensory axonopathies. Cobalamin deficiency neuropathy is the exception, often presenting with a non-length-dependent sensory neuropathy. Patients with cobalamin and copper deficiency neuropathy characteristically have concomitant myelopathy, whereas vitamin E deficiency is uniquely associated with a spinocerebellar syndrome. In contrast to those nutrients for which deficiencies produce neuropathies, pyridoxine toxicity results in a non-length-dependent sensory neuronopathy. Deficiencies occur in the context of malnutrition, malabsorption, increased nutrient loss (such as with dialysis), autoimmune conditions such as pernicious anemia, and with certain drugs that inhibit nutrient absorption. When promptly identified, therapeutic nutrient supplementation may result in stabilization or improvement of these neuropathies.

Hematopoyesis extramedular pleural secundaria a anemia perniciosa grave / Pleural extramedullary hematopoiesis due to severe pernicious anemia

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