Untreated Pernicious Anemia Research Articles

Newly Diagnosed Pernicious Anemia Can be Treated with a Single Megadose of Cobalamin. Results of a Pilot Trial

Introduction: Pernicious anemia is the leading cause of vitamin B12 deficiency worldwide, caused by an autoimmune reaction against parietal cells in the gastric mucosa leading to B12 absorption impairment. The treatment of pernicious anemia is based on replacement of cobalamin, oral and sublingual routes have been described nevertheless its absorption is erratic. The recommended schedules for vitamin B12 replacement is an intramuscular injection of 1000μg every other day for 1 to 2 weeks followed by weekly injections for a month and then tapered to once a month indefinitely (Green.Blood 2017;129(19):2603-2611). Such an approach can limit treatment adherence for patients in a resource-poor setting and may be unnecessary. Furthermore, the toxicity of cobalamin is minimal, while the benefit of larger doses is unknown.Objective: We aim to demonstrate that a single mega-dose intramuscular (IM) injection of a multivitamin formulation is sufficient to achieve and maintain a complete hematologic response for a six-month period.Methods: We performed a single center pilot study approved by our ethics committee and registered in Clinicaltrials.gov (NCT03372447). All patients with newly diagnosed, untreated pernicious anemia ≥18 years were included after written informed consent was obtained. A single IM dose of a multivitamin formulation consisting on cobalamin 10,000 μg, thiamin 100 mg, and pyridoxine 50 mg was administered. Complete blood count (CBC) was performed at 15 and 30 days and monthly thereafter for a total of six months. Partial response (PR) was considered when Hb ≥10g/dl, Normal WBC, PLT ≥100x103/μL, Complete response (CR) was defined as Hb ≥12g/dl, normal WBC and PLT. Our primary outcome was normalization of CBC (CR) at 6 months. As secondary outcomes we evaluated safety and measured levels of methylmalonic acid (MMA), homocysteine (HCY) and B12 levels (B12L) at diagnosis, three and six months after treatment.Results: Eight patients have been enrolled (5 men and 3 women), median age was 58 years (range 25-77). None had neurological symptoms at presentation. Median laboratory values at diagnosis were Hb 5.9 g/dL (range 3.9-10.7), mean corpuscular volume 113.2 fL (range 94.6-122.9), WBC 2.68x103/μL (range 1.26-6.08), PLT 93x103/μL (range 9.75-156,000), lactic dehydrogenase 3082IU/L (range 439-9840), B12L 85 pg/ml (range 83-90), HCY 154.09 μmol/L (range 83.7-182.44), MMA 24435 nmol/L (range 5175-99500). By day 30 all patients achieved PR. At the end of the third month, 100% of patients reached a CR regarding Hb and WBC while 88% of patients reached a complete PLT response. Median Hb increment at 1 month and 3 months was 6.15g/dl (range 3.1-7.74) and 1.8g/dl (range 0.4-3.7) respectively. The difference between Hb concentration at all time-points was statistically significant (ANOVA; p=0.002) particularly in the first 15 days (p=0.025), while post hoc testing revealed that increments in Hb after the second-week post-treatment were not (p>0.05). Until now, 4/8 patients have completed the primary outcome and all of them have maintained CR and normal levels of HCY and B12L without further cobalamin doses, only one patient had an asymptomatic increase of MMA. No adverse events following the administration of multivitamin preparation were documented.Conclusions: A single dose of a 10,000μg B12 multivitamin was safe and tolerated. Thus far all patients have achieved and maintained a response for at least six months. This simplified single cobalamin administration is an effective option for the treatment of pernicious anemia. [Display omitted] DisclosuresGomez-Almaguer:AbbVie: Consultancy; Novartis: Consultancy.

"What an Affliction": Mary Todd Lincoln's Fatal Pernicious Anemia.

To date, no single diagnosis has unified the psychiatric illness and the numerous poorly defined physical complaints that Mary Lincoln (née Todd, 1818-1882) suffered in adulthood. Here, I show that her physical ailments spanned 30 years and included sore mouth, pallor, paresthesias, the Lhermitte symptom, fever, headaches, fatigue, resting tachycardia, edema, episodic weight loss, progressive weakness, ataxia, and visual impairment. Long thought hypochondriacal, these findings, plus their time course and her psychopathology (irritability, delusions, hallucinations, with preserved clarity), are all consistent with vitamin B12 deficiency. Pernicious anemia most probably caused this deficiency: she lacked risk factors for other causes, and her consanguineous parents both derived from a region of Scotland having a high incidence of pernicious anemia. A diagnosis of chronic multisystem pernicious anemia would clarify the conduct of Mary Lincoln as First Lady and widow, and illuminate challenges faced by her husband, President Abraham Lincoln. Her case highlights many forgotten features of the natural history of untreated pernicious anemia and is unique in the medical literature in demonstrating such a course extending over a lifetime.

Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms

Severe vitamin B(12) deficiency produces a cluster of neurological symptoms in infants, including irritability, failure to thrive, apathy, anorexia, and developmental regression, which respond remarkably rapidly to supplementation. The underlying mechanisms may involve delayed myelination or demyelination of nerves; alteration in the S-adenosylmethionine:S-adenosylhomocysteine ratio; imbalance of neurotrophic and neurotoxic cytokines; and/or accumulation of lactate in brain cells. This review summarizes the current knowledge concerning infantile vitamin B(12) deficiency, including a pooled analysis of case studies of infants born to mothers with untreated pernicious anemia or a strict vegetarian lifestyle and a discussion of the mechanisms that may underlie the manifestations of deficiency.

Influence of cobalamin deficiency compared with that of cobalamin absorption on serum holo-transcobalamin II

Cobalamin attached to transcobalamin II (TC II), known as holo-TC II, is the active cobalamin fraction taken up by tissues. Holo-TC II is also the form in which absorbed cobalamin enters the circulation from the ileum. Therefore, holo-TC II has been proposed variously as a marker of cobalamin adequacy, cobalamin absorption, or both, including even its advocacy as a surrogate Schilling test. Such claims carry conflicting diagnostic implications because metabolic adequacy and absorption are not identical. The objective was to examine metabolic and absorptive influences on holo-TC II. Treated patients with pernicious anemia (PA), who have abnormal absorption but a normal metabolic status, were chosen as the model to differentiate between the effects of the 2 cobalamin-related characteristics. Serum holo-TC II and indexes of cobalamin metabolism in 23 treated patients were compared with those of 6 untreated PA patients (abnormal absorption and metabolic status) and 33 control subjects (normal absorption and metabolic status). Holo-TC II, which correlated directly with cobalamin and inversely with homocysteine, was significantly higher in treated PA patients in metabolic remission than in untreated PA patients (74 +/- 59 compared with 9 +/- 6 pmol/L) and was significantly lower than in control subjects (105 +/- 58 pmol/L), although the latter difference was small and the values overlapped greatly. Metabolic cobalamin status is a major determinant of serum holo-TC II. Absorption status may have mild influence as well, although other explanations remain possible. Serum holo-TC II cannot be used clinically to diagnose cobalamin malabsorption because of overlap with normal values. The influences on holo-TC II are complex and require careful analysis.

Non-transferrin-bound serum iron (NTBI) in megaloblastic anemia: effect of vitamin B(12) treatment.

The abnormalities in iron metabolism associated with megaloblastic anemia are rapidly reversed by B(12) therapy in pernicious anemia (PA). Although non-tranferrin-bound plasma iron (NTBI) was previously shown to be associated with severe iron overload, its origin is unknown. Four patients with PA were studied before and after B(12) treatment. NTBI was measured by a fluorescence-based one-step assay. All patients had very high transferrin saturation, NTBI values ranging from 1.1 to 2.6 micromol/l and normal serum ferritins. B(12) treatment resulted in the disappearance of NTBI and normalization of transferrin saturation within 22-42 h. The prompt disappearance of NTBI following B(12) therapy implicates catabolic iron derived from ineffective erythropoiesis as the major source of NTBI in untreated PA and possibly in thalassemia major and sideroblastic anemia. Our findings offer further insight into the pathogenesis of NTBI in diseases associated with abnormal erythropoiesis.

The Danger of B12 Deficiency in the Elderly

Vitamin B12 deficiency damages nerve cells and aggravates nervous system disorders even in the absence of evidence of anaemia. Prevalence of B12 deficiency increases with age especially over 65 and is frequently associated with Alzheimer's disease. Recent American surveys record a higher prevalence of B12 deficiency and of undiagnosed and untreated pernicious anaemia in the elderly than reported earlier. B12 deficiency is also reported to be a risk factor for heart disease, stroke and accelerated ageing.

Prevalence of undiagnosed pernicious anemia in the elderly

Background : Existing information about the prevalence of pernicious anemia is largely based on older surveys that favored florid manifestations, tended to be retrospective analyses of previously diagnosed disease, and usually studied homogeneous European populations. The lack of current data in the United States has, among other things, hampered discussions of the proposal to increase folate intake by the general population. Objective : To estimate the prevalence of undiagnosed and untreated pernicious anemia among the elderly. Methods : A prospective survey of cobalamin levels and anti-intrinsic factor antibody was done in the elderly. Blood testing was done in 729 people aged 60 years or older and follow-up assessment with the Schilling test and other tests was offered when results were abnormal. Resuts : Seventeen subjects were found to have pernicious anemia, usually with only minimal clinical manifestations of cobalamin deficiency. Although cobalamin deficiency had been suspected by the physicians of three subjects, they had been treated inadequately and still had evidence of deficiency. Excluding these three partially treated subjects from the analysis, 1.9% of the survey population had unrecognized and untreated pernicious anemia. The prevalence was 2. 7% in women and 1.4% in men ; 4.3% of the black women and 4.0% of the white women had pernicious anemia. Conclusions : Undiagnosed pernicious anemia is a common finding in the elderly, especially among black and white women. If these findings can be extrapolated, almost 800 000 elderly people in the United States have undiagnosed and untreated pernicious anemia, and, thus, would be at possible risk for masked cobalamin deficiency if exposed to large amounts of folate. This number does not include those elderly with cobalamin deficiency caused by other disorders or the still unknown number of younger people with unrecognized pernicious anemia and other causes of deficiency.

Prevalence of Undiagnosed Pernicious Anemia in the Elderly

Existing information about the prevalence of pernicious anemia is largely based on older surveys that favored florid manifestations, tended to be retrospective analyses of previously diagnosed disease, and usually studied homogeneous European populations. The lack of current data in the United States has, among other things, hampered discussions of the proposal to increase folate intake by the general population. To estimate the prevalence of undiagnosed and untreated pernicious anemia among the elderly. A prospective survey of cobalamin levels and anti-intrinsic factor antibody was done in the elderly. Blood testing was done in 729 people aged 60 years or older and follow-up assessment with the Schilling test and other tests was offered when results were abnormal. Seventeen subjects were found to have pernicious anemia, usually with only minimal clinical manifestations of cobalamin deficiency. Although cobalamin deficiency had been suspected by the physicians of three subjects, they had been treated inadequately and still had evidence of deficiency. Excluding these three partially treated subjects from the analysis, 1.9% of the survey population had unrecognized and untreated pernicious anemia. The prevalence was 2.7% in women and 1.4% in men; 4.3% of the black women and 4.0% of the white women had pernicious anemia. Undiagnosed pernicious anemia is a common finding in the elderly, especially among black and white women. If these findings can be extrapolated, almost 800000 elderly people in the United States have undiagnosed and untreated pernicious anemia, and, thus, would be at possible risk for masked cobalamin deficiency if exposed to large amounts of folate. This number does not include those elderly with cobalamin deficiency caused by other disorders or the still unknown number of younger people with unrecognized pernicious anemia and other causes of deficiency.

Cobalamin‐dependent metabolism in chronic myelogenous leukemia determined by deoxyuridine suppression test and the formiminoglutamic acid and methylmalonate excretion in urine

The cobalamin metabolism in chronic myelogenous leukemia (CML) was evaluated in 18 newly diagnosed and untreated patients by formiminoglutamic acid (FiGlu) and methyl malonic acid excretion (MMA) tests. A deoxyuridine (dU) suppression test of bone marrow cells was compared in patients with acute myelogenous leukemia (N = 5), myelodysplastic disease (N = 3), untreated pernicious anemia (N = 16), folate deficiency (N = 7), and a hospital reference group without signs of cobalamin or folate deficiency (N = 22). All had normal MMA excretion but 3 of 15 patients had increased FiGlu excretion. In vitro thymidine uptake in bone marrow cells of CML patients were lower (mean 40 fmol/106 cells) than pernicious anemia patients (115 fmol/106 cells). Methotrexate (MTX) increased the uptake in all cases. Addition of formyl-THF, methyltetrahydrofolate (methyl-THF), and pteroylglutamic acid (PGA) tended to normalize the effect of MTX. In pernicious anemia methyl-THF only decreased the uptake in combination with CN-Cbl. dU suppression values were significantly higher (6.3%) in CML than in the reference group (4.4%), but significantly lower than in pernicious anemia (41.6%) and folate deficiency (28.5%). The dU suppression values in bone marrow cells of CML patients correlated significantly with the transferrin saturation. In buffy coat cells dU suppression values were even higher (9.3%) than in bone marrow cells of the same CML patients. Addition of folate forms and CN-Cbl did not change the dU suppression values in CML, as it did in pernicious anemia. MTX increased dU suppression values significantly in all patients, but more in CML (64.5%) than in pernicious anemia (48.6%) and controls (49.8%). The MTX effect was to some extent neutralized by folate analogues with formyl-THF as the most effective followed by methyl-THF and lastly PGA. Methyl-THF also neutralized MTX in pernicious anemia, but its effect was certainly enhanced by addition of CN-Cbl. Thymidine uptake and dU suppression patterns were not significantly changed in CML after treatment with busulfan for 1 week or in accelerated phase. We concluded that signs of cobalamin or folate deficiency (apart from one patient) cannot be demonstrated in untreated CML. However, dU suppression was significantly increased and more so in circulating myeloid cells than in bone marrow. This indicates a deranged metabolism of deoxynucleotides which is independent of cobalamin and folates, and a difference between bone marrow cells and circulating cells. dU suppression is a valuable indicator of cobalamin deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)

Functional defect of T cells in autoimmune gastritis.

The functional response and phenotypic characterisation of peripheral blood T cells were studied in 41 patients with autoimmune gastritis--nine patients with autoimmune gastritis alone, 11 with untreated pernicious anaemia, and 21 with resolved pernicious anaemia who were taking vitamin B-12. Phenotypic analysis showed no changes in the CD4/CD8 ratio in any group of patients. CD3+ cells were significantly decreased and CD16+ cells were significantly increased in patients with autoimmune gastritis alone. Phytohaemagglutinin induced T cell proliferation, with or without interleukin 2, was reduced in the three groups. T cell proliferation induced by phorbol myristate acetate was normal. Interleukin 2 production of phytohaemagglutinin-stimulated lymphocytes was normal in the three groups. Five patients with pernicious anaemia treated with vitamin B-12 were followed and persistent hypoproliferation of T cells in response to phytohaemagglutinin was observed. The follow up study of the phenotype of these patients showed a significant increase of the CD2+ CD3- lymphocyte population after six months' treatment. In conclusion, the three groups of autoimmune gastritis patients studied have a functional defect in T cells that is independent of B-12 treatment and of the presence of pernicious anaemia.

Autoimmune cytopenias in pernicious anemia: A report of four cases and review of the literature

Pernicious anemia appears to be autoimmune in origin and is associated with immune disorders of several organ systems. We report 4 patients with pernicious anemia and immune cytopenias, an association that may sometimes pose diagnostic problems unless specifically considered. Pernicious anemia coexisted with or was closely followed by idiopathic thrombocytopenic purpura in 3 patients and by autoimmune hemolytic anemia in a 4th patient. In addition to cobalamin therapy, all patients required corticosteroids (2 also received danazol), while 1 also required splenectomy. All 4 patients were women. The 3 patients with idiopathic thrombocytopenic purpura were also blood group O and were iron-deficient. Autoimmune cytopenias may occur in patients with treated or untreated pernicious anemia and require specific therapy.

Red blood cell distribution width in untreated pernicious anemia.

The red blood cell distribution width (RDW) was studied in 26 unselected patients with untreated pernicious anemia. RDW changes were also sequentially followed after therapy in 12 patients. The mean (+/- 1 SD) RDW values were significantly higher in pernicious anemia patients than in controls (21.7 +/- 9.1% vs. 13.2 +/- 1.1%, P less than 0.0001). Nevertheless, 31% of the patients had normal RDWs. There were no consistent findings among those who had normal RDW. Most of them were in the early stages of deficiency, but some had advanced deficiency. Over half of those with normal RDW also had normal mean corpuscular volume (MCV). Overall, 9 of the 26 patients (35%) had normal MCV. Of eight patients whose RDW fell with therapy, some showed a steady fall while others had a transient rise followed by a progressive drop. Despite current advocacy that a high RDW is a sensitive and consistent finding in vitamin B12 deficiency, our findings show that a large proportion of untreated pernicious anemia patients have normal RDWs and that in contrast to iron deficiency, elevation of RDW is not necessarily the earliest indicator of vitamin B12 deficiency.

Increased urinary excretion of formiminoglutamic acid in nitrous-oxide-treated rats and its reduction by methionine.

Inhalation of nitrous oxide oxidises cob(I)alamin and inactivates methionine synthetase of which cobalamin is a co-enzyme. The biochemical changes in the rat following exposure to nitrous oxide resemble in some detail the changes present in patients with untreated pernicious anemia due to deficiency of cobalamin. There is a marked increase in the excretion of formiminoglutamic acid in the urine following exposure to nitrous oxide. A significant decrease is produced, while on N2O, by giving methionine. The explanation for these findings is discussed in the light of recent data on the effects of cobalamin inactivation.

Transcobalamin-binding capacities in vitamin B12-related diseases.

Abnormalities in some transcobalamin unsaturated binding capacities (TC-UBBC) were found in some patients with treated pernicious anemia who had elevated TC II-UBBC, R-UBBC, and total UBBC, in gastrectomized patients with latent vitamin B12 deficiency who had elevated R-UBBC and UBBC, and in patients with obstructive jaundice who had elevated TC II-UBBC and UBBC. No abnormalities were found in patients who had untreated pernicious anemia, folate deficiency, unclassifiable megaloblastic anemia, tobacco amblyopia, or low serum B12 level but normal capacity to absorb vitamin B12.

Marrow Cells from Patients with Untreated Pernicious Anaemia Cannot Use Tetrahydrofolate Normally

Folate analogues were added to human bone marrow cells to determine their effect on deoxyuridine utilization in the deoxyuridine suppression test. Formyltetrahydrofolates fully corrected the impairment of dU utilization in pernicious anaemia marrows but tetrahydrofolate was relatively ineffective. All these analogues were effective in megaloblastic marrows from folate deficient patients. Formyltetrahydrofolates also enhanced dU utilization by normal human marrows whereas methyltetrahydrofolate reduced its use. In terms of the methylfolate trap hypothesis, the expectation that cobalamin-deficient marrows would be able to use tetrahydrofolate normally was not realized.

Arginine methyltransferase activity in chronic erythremic myelosis (Diguglielmo syndrome)

Activity of S- adenosylmethionine-dependent arginine methyltransferase was substantially higher in sonicated bone marrow samples from 6 patients with chronic erythremic myelosis than in bone marrow from 3 patients with untreated pernicious anemia, 2 patients with autoimmune hemolytic anemia, and 4 normal persons. Increased activity of this enzyme may be one of the factors contributing to the pathogenesis of methylated arginines in histones of erythroblasts from patients with chronic erythremic myelosis.

N5-Methyltetrahydrofolate-Homocysteine Cobalamin Methyltransferase Activity in Chronic Erythremic Myelosis (Di Guglielmo Syndrome)

SummaryActivity of N5-methyltetrahy-drofolate-homocysteine cobalamin methyl-transferase was determined in sonicates of bone marrow obtained from five patients with chronic erythremic myelosis (Di-Guglielmo syndrome), three patients with severe untreated pernicious anemia, and eight normal persons. In four of the five patients with chronic erythremic myelosis, enzymatic activity was higher than in normals, and addition of methylcobalamin did not affect enzymatic activity, suggesting that the enzyme exists as the holomethyltransfer-ase. Increasing essential substrates such as S-adenosylmethionine, homocysteine, and methyltetrahydrofolate to fourfold the level used in the standard assay did not affect enzymatic activity significantly. Increased activity of this enzyme in chronic erythremic myelosis may relate to the high proliferative capacity reflected by increased cell turnover and intramedullary cell death.

Nonspecific Esterase Activity in Pernicious Anemia and Chronic Erythremic Myelosis: A Cytochemical and Electrophoretic Study

Cytochemically, nonspecific esterase activity was detected in megaloblasts from three patients with severe untreated pernicious anemia, in megaloblastoid erythroblasts from five patients with chronic erythremic myelosis (DiGuglielmo syndrome), and in normoblasts from a patient with severe untreated iron-deficiency anemia. Nonspecific esterase activity in all of these erythroblasts was inhibited by sodium fluoride. Enzymatic activity could not be detected in normoblasts from normal marrows. Electrophoretically, three bands of nonspecific esterase activity could be visualized in marrow sonicates from the anemic patients and normal persons. All of these bands were inhibited by sodium fluoride. The results demonstrate that electrophoretically and in terms of fluoride inhibition, nonspecific esterases obtained primarily from erythroid precursors in various types of anemias are similar to nonspecific esterases found in normal marrows presumably containing a more heterogeneous population of cells.

Periodic Acid–Schiff-positive Megaloblasts in Pernicious Anemia

Periodic acid-Schiff-positive material representing glycogen was found in bone marrow megaloblasts at all stages of maturation from 11 patients with severe untreated pernicious anemia. This accumulation of glycogen in megaloblasts, which are known to have disordered biosynthesis of DNA, RNA, and histones, suggests that carbohydrate metabolism may also be abnormal in vitamin B12 deficiency, perhaps as a result of an abnormality in the enzyme amylophosphorylase.

Abnormal folate polyglutamate ratios in untreated pernicious anaemia corrected by therapy.

The relative amounts of folate compounds having 1--3--, 4--, 5-- and 6--glutamic acid residues in the molecule were measured in red blood cells. The results were expressed in relation to methyltetrahydrofolate pentaglutamate (5-glutamic acid residues) which is the analogue present in highest concentration. When the concentration of pentaglutamate is given a value of 100 the relative concentration of folates with 1--3--, 4--, 5-- and 6--glutamic acid residues in control subjects are 48, 48, 100 and 50 respectively. In folate deficiency there is a fall in the relative amount of the short chain glutamic acid chain compounds in addition to having an overall fall in the amount of folate present, the values for 1--3, 4, 5 and 6 chain folates being 16, 14, 100 and 39. By contrast, in untreated pernicious anaemia there is an accumulation of the short chain folates as well as an overall fall in polyglutamate concentration and the relative concentrations were 72, 44, 100 and 30. Folate polyglutamate appears to be the active coenzyme and the reltive amounts of glutamic acid residues may serve to regulate the rate of enzyme activity. In pernicious anaemia the amount of enzyme is reduced and on this hypothesis the regulatory function impaired.