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.

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.

[Successful treatment with mecobalamin in a pernicious anemia patient presenting with false-normal serum vitamin B12].

An 81-year-old woman presented to our hospital with anemia. Complete blood counts revealed macrocytic anemia; however, serum vitamin B12 and folate levels were normal. Bone marrow aspiration revealed multilineage dysplasia, and the patient was initially diagnosed with refractory cytopenia and multilineage dysplasia subtype of myelodysplastic syndrome. However, blood smear revealed hypersegmented neutrophils and bone marrow aspiration showed remarkable megaloblastic changes of erythroid cells. Based on these findings, the patient was administered 1,500 µg mecobalamin per day on a trial basis. Three weeks after initiating mecobalamin, macrocytic anemia improved. Her hemoglobin levels were also normalized along with immediate resolution of peripheral blood dysplasia. The final diagnosis was pernicious anemia (PA) based on anti-intrinsic factor positivity and the efficacy of mecobalamin. Use of automated analyzers may be associated with falsely normal or falsely elevated vitamin B12 levels in the presence of anti-intrinsic factor antibodies. Our case suggests that trial administration of mecobalamin may be an important step to correctly diagnose PA associated with falsely normal or falsely elevated vitamin B12 levels, particularly when typical morphological features of PA are present.

B12 deficiency leading to marked poikilocytosis versus true schistocytosis, a pernicious problem.

Severe vitamin B12 deficiency is caused most commonly by autoimmune atrophic gastritis leading to loss of intrinsic factor. Vitamin B12 deficiency leading to megaloblastic anemia and demyelinating central nervous system disease is well known; however, a rare presentation of B12 deficiency described as pseudothrombotic microangiopathy is not well known. This complication presents with signs of mechanical hemolysis, elevated lactate dehydrogenase (LDH), thrombocytopenia, and a low reticulocyte count, which can be incorrectly diagnosed as thrombotic thrombocytopenic purpura and managed incorrectly. Decreased reticulocyte count and an LDH >2500IU/L is more commonly seen in B12 deficiency. However, recognizing the differences in marked poikilocytosis can be challenging, as seen with megaloblastic changes and true schistocytosis. To illustrate the challenge in differentiating between megaloblastic changes and true schistocytosis, we present the case of a 27-year-old woman who presented to her physician for symptomatic anemia and complaints of nausea, vomiting, and loose stool. She had a hemoglobin of 5.1g/dL, platelet count of 39×109/L, LDH of 9915IU/L, haptoglobin below assay limit, and a reticulocyte count of 2.5%. Peripheral smear showed macrocytic anemia, rare hypersegmented neutrophils, and schistocytes. Vitamin B12 level was less than 50pg/mL, methylmalonic acid was 0.33µmol/L, anti-parietal cell antibody was >1:640, and intrinsic factor blocking antibody was positive-confirming the diagnosis of pernicious anemia. While hospitalized, she was treated with vitamin B12 1000µg intramuscular injections daily and thereafter continued with monthly injections, which ultimately resolved her severe macrocytic anemia.

A rare form of anemia in systemic lupus erythematosus.

Mechanisms responsible for anemia in systemic lupus erythematosus (SLE) can be immune or non-immune. A 27-year-old previously healthy woman was admitted with echymotic patches over the lower limbs for six months, multiple joint pain and fatigue for 2 months. She had severe pallor and multiple echymotic patches over the lower limbs. She was diagnosed with SLE with pernicious anemia and iron deficiency anemia. The rare association of SLE with pernicious anemia was reported previously in few patients. Treatment of SLE along with B12 supplementation is necessary for such patients. Since etiology for anemia in SLE can be of various kinds, a detailed workup for identifying the underlying mechanism is necessary.

Differentiation of pernicious anemia from thrombotic thrombocytopenic purpura: The clinical value of subtle pathologic findings.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a microangiopathic hemolytic anemia that requires emergent treatment with plasma exchange and is one of the most important conditions for which apheresis service professionals are consulted. Careful interpretation of initial laboratory values and the peripheral blood smear is a critical first step to determining the need for plasma exchange because other conditions can show deceptively similar red cell morphology, and ADAMTS13 levels are often not rapidly available. CASE REPORT: We report a case of a patient who was initially diagnosed with TTP and treated with plasma exchange based on preliminary laboratory data and a peripheral blood smear that contained bizarre microcytic red blood cells presumed to be schistocytes. The peripheral blood smear was later interpreted by the hematopathologist to be inconsistent with TTP, and further workup led to a diagnosis of severe vitamin B12 deficiency secondary to pernicious anemia. RESULTS AND CONCLUSION: This case highlights the diagnostic complexity of thrombotic microangiopathies and the importance of a critical evaluation of the blood smear and presenting laboratory data when there is a concern for TTP.

High percentage of regulatory T cells before and after vitamin B12 treatment in patients with pernicious anemia.

INTRODUCTION: In some previous studies, vitamin B12 treatment showed immunomodulatory effects and restored the immunological abnormalities in patients with pernicious anemia (PA). In the present study, peripheral blood T cell subsets, including regulatory T cells (T(reg)s), were examined before and after vitamin B12 treatment in PA patients. PATIENTS AND METHODS: The percentages of CD4, CD8, Th1, Th2 and T(reg)s were examined in 23 PA patients before vitamin B12 treatment, in 23 other PA patients after vitamin B12 treatment and in 28 healthy controls. RESULTS: The mean percentage of CD8+ T cells was significantly higher in the control group (23.0%; 95% CI, 20.4-25.6%) than in the pre- (16.0%; 95% CI, 12.1-20.0%) and posttreatment groups (15.2%; 95% CI, 11.8-18.6%; p < 0.05). The CD4/CD8 ratio was significantly lower in the control group (2.01; 95% CI, 1.66-2.34) than in the pre- (3.45; 95% CI, 2.55-7.80) and posttreatment groups (2.97; 95% CI, 2.22-3.72; p < 0.05). There was no significant difference in the mean Th1/Th2 ratio among these groups. There were significant increases in the mean percentage of T(reg)s in the pre- (6.29%; 95% CI, 5.04-7.54%) and posttreatment groups (7.77%; 95% CI, 6.34-9.20%) compared with the control group (4.18%; 95% CI, 3.92-4.47%; p < 0.05). CONCLUSIONS: The percentage of T(reg)s was significantly higher in PA patients than in normal subjects, and this high T(reg) percentage was not different before and after vitamin B12 treatment. Other immunological alterations also did not recover after vitamin B12 treatment, so that these immunological changes appear to be the cause of PA and are not induced by vitamin B12 deficiency.

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.

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.

Challenging illness scripts: a case of pernicious anaemia and axonal neuropathy.

This case report presents a male in his 30s with pernicious anaemia, initially diagnosed with autoimmune haemolytic anaemia and thrombocytopenia. Despite improvement with treatment, he developed bilateral leg weakness and numbness, ultimately diagnosed as peripheral neuropathy. Further investigations revealed a spectrum of haematological and neurological manifestations associated with B12 deficiency, challenging the typical illness script of pernicious anaemia. This report underscores the importance of recognising variations in clinical presentation and highlights the need for expanded illness scripts to guide accurate diagnosis and management.

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.

Erythema nodosum and pernicious anemia.

Erythema nodosum (EN) often presents as a sudden onset of tender, erythematous, subcutaneous nodules on the legs and ankles. Although rare, pernicious anemia may be related to vitamin B12 deficiency. Discussion of this association in the context of a particular patient is presented.

[Mecobalamin improved pernicious anemia in an elderly individual with Hashimoto's disease and diabetes mellitus].

A 73-year-old Japanese man with Hashimoto's disease and diabetes mellitus received regular medical checkups for type 2 diabetes care. Blood tests indicated macrocytic anemia (red blood cell count, 279×104 /µL; hemoglobin, 12.2 g/dL; hematocrit, 34.0%; mean corpuscular volume, 121.9 fL). The laboratory data demonstrated a normal folic acid level with a low vitamin B12 level. An endoscopic examination indicated no signs of gastric or intestinal bleeding. Positive results for anti-intrinsic factor antibodies were strongly suggestive of pernicious anemia. The patient refused cobalamin injections to treat the anemia. However, the oral administration of mecobalamin for the treatment of diabetic neuropathy was simultaneously initiated. Subsequently, the anemia gradually improved. Oral mecobalamin was presumably effective for pernicious anemia management. Anemia is frequently observed in elderly patients, and the incidence of pernicious anemia increases with age. Anemia is conventionally treated with cobalamin injections. Currently, the oral administration of mecobalamin is not the typical treatment for anemia. However, as in our case, a few reports have documented positive results following oral mecobalamin treatment. Moreover, oral mecobalamin is a fairly recent, novel, noninvasive mode of treatment, making it ideal for elderly patients, who are generally frail. This case suggests the efficacy of mecobalamin for the treatment of pernicious anemia.

[History of the therapy of pernicious anemia]. / Az anaemia perniciosa terápiájának története.

Increased blood cell regeneration in exsanguinated experimental animals treated either with liver or with aqueous liver extracts was reported by Whipple and by Jeney and Jobling, respectively. These findings stimulated Minot and Murphy to provide evidence for the efficacy of liver against anaemia in clinical studies. After oral administration of liver (45-50 g per day) for 45 patients with anaemia perniciosa improvement of the hematological status was demonstrated. Consequently, for proving the therapeutic value of liver therapy Whipple, Minot and Murphy received Nobel price in 1934. The isolation of the antianemic factor from the liver has been succeeded in 1948 and designated as vitamin B12. At the same time Lucy Wills applied yeast for the treatment of pregnant women with anemia related to undernourishment. The conclusions of this study inspired the discovery of folate. The detailed investigation of the mode of action of vitamin B12 and folate enriched our knowledge in the area of pathophysiology and extended the clinical application of these two drugs.