Vitamin B12: For more than just the treatment of megaloblastic anemia?

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Anti-H2: type 2 histamine receptor antagonists; IF: intrinsic factor; HCl: hydrochloric acid; PPI: proton pump inhibitors; RDI: recommended daily intake; IM: intramuscular; SC: subcutaneous; TCII: transcobalamin II; Vit. B12: vitamin B12." ] ] ] "textoCompleto" => "IntroductionVitamin B12, or cobalamin, belongs to the group of water-soluble vitamins that play a role in myelin formation, red blood cell maturation, and nucleic acid synthesis. It is synthesized exclusively by bacteria and is obtained through the intake of foods derived from animals, such as eggs, milk and dairy products, red meat and poultry, liver (mainly beef liver), fish, and seafood, among other sources. Our gut microbiota is insufficient for producing the vitamin B12 necessary to meet daily needs, which vary according to age and condition. In general, the daily recommended intake is 2.4 μg/day for adults 2.8 μg/day during pregnancy and breastfeeding.In order for it to be absorbed during digestion, there must be hydrochloric acid and pepsin that break down proteins in the diet, thus releasing the cobalamin, and a protein called intrinsic factor (IF), which binds to it forming the IF + B12 complex. This protects it until the terminal ileum, where it passes into the blood through active transport after binding to cubam receptors located in the membrane of enterocytes. Only 1% is absorbed through passive diffusion (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). It arrives to the liver through the portal system bound to holotranscobalamin, transforming into its two biologically active forms: methylcobalamin and 5′-deoxyadenosylcobalamin, a part of which is stored in the hepatocyte as adenosylcobalamin.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Liver cobalamin reserves allow for several years of little or no vitamin B12 intake before signs of vitamin B12 deficiency appear. In systemic circulation, cobalamin is bound to transcobalamin II and disseminates through tissues, including the central nervous system. It passes to the cell interior through endocytosis through CD320 receptors.Vitamin B12 is mainly excreted through the biliary tract via enterohepatic circulation, through which a part is reabsorbed and another is eliminated (30%–60% of daily oral intake) in the feces. The amount of B12 left over after its distribution through the body—a small percentage—is eliminated through the renal pathway.Its clinical indication is for the treatment of hypovitaminosis B12. It is administered orally or intramuscularly in the form of hydroxocobalamin (Megamilbedoce® which contains 10,000 μg of hydroxocobalamin in 2-mL ampoules) or cyanocobalamin (Optovite B12® which contains 1000 μg of cyanocobalamin in 2-mL ampoules). The two available presentations are stable and water-soluble. They are mainly administered intramuscularly and orally when no diseases or conditions which decrease its enteral absorption are present. According to the technical datasheets of both presentations, intravenous administration is not recommended (except in the case of extreme thrombocytopenia, according to both datasheets) due to the risk of anaphylaxis.To date, no vitamin B12 toxicity has been described except for allergy to the cobalt present in the molecule, the prevalence of which in Spain is estimated to be 10.8% of all patients who visit a skin allergy unit<a class="elsevierStyleCrossRef" href="#bib0005">1</a>. It is a type IV allergy mediated by T-CD4 lymphocytes.The range of vitamin B12 concentration in the blood considered normal is between 150 and 900 pg/mL, approximately, depending on the particular laboratory. Two clinical conditions may occur: one caused by a cobalamin deficit (≤150 pg/mL)<a class="elsevierStyleCrossRef" href="#bib0010">2</a> which is the most commonly and best studied, and one caused by an excess of vitamin B12 (>900 pg/mL).Currently, the determination of serum vitamin B12 levels are routinely measured in our setting using automatized immunochemiluminescence methods that are widely used due to their speed, economy, and reliability<a class="elsevierStyleCrossRef" href="#bib0010">2</a>.Hypovitaminosis B12Hypovitaminosis B12 is the most known and studied form of vitamin B12 level abnormalities. It mainly occurs due to a deficit in dietary intake, such as in malnutrition, vegetarian or vegan individuals, older adults, pregnant individuals, or individuals with alcohol use disorder; in ailments in which its intestinal absorption is decreased, such as in atrophic gastritis, intestinal malabsorption syndrome, and gastrointestinal surgery; associated with the intake of certain drugs, such as antacids, proton pump inhibitors, or metformin; and in some other rare genetic diseases, such as Imerslund-Gräsbeck syndrome, an anomaly of vitamin B12 receptors located on the enterocytes of the terminal ileum that impede their absorption of the IF + B12 complex (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>One segment of the population in which hypovitaminosis B12 is very common is older adults. This has a two-part origin: deficient intake in the diet due to inadequate nutrition together with malabsorption syndrome, as both the secretion of gastric hydrochloric acid and the number of enterocytes in the terminal ileum are diminished; both are phenomena caused by the deterioration the digestive mucosa undergoes with age<a class="elsevierStyleCrossRef" href="#bib0015">3</a>.To establish the most reliable diagnosis of hypovitaminosis B12, it is not only necessary to have levels of the vitamin in the blood, but also to measure methylmalonic acid (MMA) in the urine. MMA is a very specific analytical finding<a class="elsevierStyleCrossRef" href="#bib0020">4</a> and is even more specific than the determination of homocysteine in the blood, which may be subject to changes that are independent from a cobalamin deficit. Elevated MMA is an early sign that allows for detecting subclinical hypovitaminosis B12, but its analytical determination is not available at all healthcare centers due to the complexity of its analysis<a class="elsevierStyleCrossRef" href="#bib0020">4</a>.If hypovitaminosis B12 is not diagnosed or treated in time, megaloblastic anemia, peripheral neuropathy, vision disorders that may lead to blindness, dementia, psychotic episodes, coma, and death in extreme situations may occur.All cases of hypovitaminosis B12 require treatment with cobalamin supplements. Oral treatment is sufficient for most, unless there is difficulty in its digestive absorption due to, for example, pernicious anemia or gastrointestinal surgery with iliac resection. In these cases, intramuscular administration of hydroxocobalamin or cyanocobalamin is necessary. Some authors recommend high doses of oral B12 (1000–2000 μg/day) in these cases, attempting to maximize the 1% that is absorbed through simple diffusion<a class="elsevierStyleCrossRef" href="#bib0025">5</a>.In recent years, numerous observational studies, including a meta-analysis of results, have found a significant association between low levels of cobalamin in the blood and mood abnormalities, depression, and cognitive impairment in both older adults and young people, regardless of whether megaloblastic anemia was present beforehand<a class="elsevierStyleCrossRefs" href="#bib0030">6–10</a>. It is known that a cobalamin deficit induces brain damage, with neuron demyelination and a reduction in neurotransmitter synthesis in the CNS<a class="elsevierStyleCrossRef" href="#bib0055">11</a>.Other observational studies have reported that the administration of B12 supplements was associated with an improvement in cognitive abilities in patients with depression and dementia, including Alzheimer’s disease<a class="elsevierStyleCrossRefs" href="#bib0060">12,13</a>. One study highlighted that in the initial stages of Alzheimer’s disease, the administration of cobalamin reduced the progression of brain atrophy as observed through neuroimaging techniques<a class="elsevierStyleCrossRef" href="#bib0070">14</a>.However, it has not yet been conclusively demonstrated that vitamin B12 supplements are useful in the treatment of depression and dementia. The results of a meta-analysis published in the Cochrane Library<a class="elsevierStyleCrossRef" href="#bib0075">15</a> that encompassed 28 studies and more than 83,000 patients with cognitive and mood problems showed no evidence of a statistically significant improvement following administration of B12 supplements.Another meta-analysis and systematic review that included 16 clinical trials with 6276 participants published afterwards concluded that B12 supplementation is probably ineffective for improving cognitive function and depressive symptoms in patients without advanced neurological disorders<a class="elsevierStyleCrossRef" href="#bib0080">16</a>.In light of the relationship observed between high serum levels of homocysteine, an amino acid that is potentially neurotoxic that tends to accompany B12 deficit, and the onset of dementia<a class="elsevierStyleCrossRef" href="#bib0085">17</a>, the impact of B12 supplementation on homocysteine levels and the onset of cognitive abnormalities was evaluated. However, the results of a systematic review with a meta-analysis showed that the administration of B12 reduced the level of homocysteine in the blood but did not improve the cognitive condition of participating subjects<a class="elsevierStyleCrossRef" href="#bib0090">18</a>. Despite the available data on vitamin B12 and cognitive impairment, this issue remains unresolved. The origin of the disparity in different studies’ results may lie in the methods used by the various authors and is a problem that must be resolved in future research.Hypervitaminosis B12Until now, hypervitaminosis B12 has been perceived as an incidental laboratory finding, scarcely studied if compared to hypovitaminosis B12 and going unnoticed most of the time. However, it has recently sparked greater interest in clinical practice. Indeed, a higher prevalence of excess cobalaminemia compared to a deficit has been described (18.5% vs. 2.2%), as was found in a recent single-center French study<a class="elsevierStyleCrossRef" href="#bib0095">19</a> with 411 vitamin B12 determinations among patients hospitalized in the internal medicine ward. On the other hand, in the BDOSE multicenter study<a class="elsevierStyleCrossRef" href="#bib0100">20</a>, which analyzed 380 B12 determinations in internal medicine patients hospitalized in 21 French hospitals, the prevalence of hypervitaminosis B12 was 18% whereas the prevalence of hypovitaminosis B12 was 71.5%. The caveat in this study is that the reason for ordering the determination of cobalaminemia levels was to screen for a deficit of said vitamin.Hypervitaminosis B12 has been detected in patients with kidney failure, liver diseases such as cirrhosis and acute-phase hepatitis, alcohol use disorder with and without liver involvement, solid tumors (lung, liver, esophagus, pancreas, and colorectal), and malignant blood disorders (chronic myelomonocytic leukemia, myeloproliferative disorders, and multiple myeloma)<a class="elsevierStyleCrossRefs" href="#bib0095">19–23</a>. What’s more, hypervitaminosis B12 has been proposed as a tumor biomarker for the diagnosis and prognosis of primary and metastatic cancer. It is a sign of a poor prognosis in metastatic cancer<a class="elsevierStyleCrossRefs" href="#bib0120">24–26</a> and its use as an acute-phase reactant in autoimmune and inflammatory diseases has been suggested<a class="elsevierStyleCrossRef" href="#bib0135">27</a>. It has also been observed that hypercobalaminemia is a sign of poor prognosis in non-oncological medical patients hospitalized in intensive care units<a class="elsevierStyleCrossRef" href="#bib0140">28</a> in addition to being a predictor of six-month mortality in older adults hospitalized in geriatrics departments<a class="elsevierStyleCrossRef" href="#bib0145">29</a>.Recently, the MMA/creatinine ratio in the blood has been proposed for detecting false B12 elevations in patients with kidney failure that may in reality be related to hypovitaminosis B12<a class="elsevierStyleCrossRef" href="#bib0150">30</a>. Said ratio has been reported to have a high specificity regardless of renal function for the detection of hypovitaminosis B12 in patients with kidney disease and vitamin levels in the low-normal range. It has been concluded that it is a promising biomarker for evaluating vitamin B12 status in questionable cases, especially when there is kidney failure<a class="elsevierStyleCrossRef" href="#bib0150">30</a>.An interesting piece of data has been reported in several recent studies that encompass broad samples of the population. These studies’ conclusions indicate that high vitamin B12 levels in the blood acted as a risk factor for the onset of lung<a class="elsevierStyleCrossRefs" href="#bib0105">21,31</a>, esophagus<a class="elsevierStyleCrossRef" href="#bib0115">23</a>, pancreatic<a class="elsevierStyleCrossRef" href="#bib0155">31</a>, and liver cancer<a class="elsevierStyleCrossRef" href="#bib0155">31</a>, but not breast cancer<a class="elsevierStyleCrossRef" href="#bib0155">31</a>. Nevertheless, more studies are required in order to obtain conclusive results in this regard. On the other hand, it has recently been published<a class="elsevierStyleCrossRef" href="#bib0160">32</a> that high serum cobalamin levels acted as a risk factor for mortality in patients with type 2 diabetes.Excess serum cobalamin depends on the underlying disease. It has been found that in liver disease and alcohol use disorder with or without liver involvement, it is due to a reduction in liver uptake and its biliary excretion. In kidney failure, the cause is an accumulation of the transcobalamin 2+ vitamin B12 complex in the blood. In hematological neoplasms, it is due to the release of the transcobalamin-B12 complex by tumor granulocytes<a class="elsevierStyleCrossRef" href="#bib0135">27</a>. What’s more, hypervitaminosis B12 may have an exogenous origin due to its continuous intramuscular administration in the treatment of pernicious anemia, for example, or oral administration in prolonged self-medication with vitamin complexes that contain B12 with the intention of preventing dementia or depression, a practice that is very popular at present.According to some authors, B12 supplements have not been studied in depth nor have they been taken into account in published studies<a class="elsevierStyleCrossRef" href="#bib0165">33</a>. The NHANES study, which included more than 24,000 participants, concluded that high vitamin B12 intake in the form of supplements was not associated with any cardiovascular adverse events or total mortality and, therefore, could be considered safe<a class="elsevierStyleCrossRef" href="#bib0170">34</a>.Lastly, when high vitamin B12 levels are persistently detected in a patient, the first course of action according to the literature should be to investigate the presence of kidney failure, liver involvement, or a possible occult solid or hematological neoplasm as the most probable causes.While the relationship between vitamin B12 and cancer is clarified, we must be reasonably prudent with the continuous administration of cobalamin, monitoring its levels if necessary, especially in subjects diagnosed with cancer or who are predisposed to developing it.FundingThis work has not received any type of funding.Conflicts of interestThe authors declare that they do not have any conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres2007171" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1719769" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2007170" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1719770" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Hypovitaminosis B12" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Hypervitaminosis B12" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Funding" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-11-04" "fechaAceptado" => "2022-11-23" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1719769" "palabras" => array:4 [ 0 => "Cyanocobalamin" 1 => "Vitamin B12 deficiency" 2 => "Hypervitaminosis B12" 3 => "Vitamin B12" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1719770" "palabras" => array:4 [ 0 => "Cianocobalamina" 1 => "Deficiencia de vitamina B12" 2 => "Hipervitaminosis B12" 3 => "Vitamina B12" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Vitamin B12, or cobalamin, belongs to the group of water-soluble vitamins and is ingested through food of animal origin such as eggs, milk, red meat and poultry, fish, and shellfish. Its clinical indication is the treatment of hypovitaminosis B12 administered orally or intramuscularly in the form of hydroxocobalamin. Hypovitaminosis B12 is mainly caused by deficient dietary intake (individuals with malnutrition, vegetarians or vegans, older adults, pregnant people, individuals with alcohol use disorder); when intestinal absorption is reduced (atrophic gastritis, malabsorption syndrome, gastrointestinal surgery); and for causes associated with the intake of drugs (antacids, metformin). Hypervitaminosis B12 has been associated with renal failure; liver diseases such as cirrhosis and acute-phase hepatitis; alcohol use disorder with or without liver involvement; solid tumors of the lung, liver, esophagus, pancreas, and colorectum; and in hematological malignancies such as leukemia and bone marrow dysplasia." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La vitamina B12 o cobalamina pertenece al grupo de vitaminas hidrosolubles y su aporte se realiza a través de la ingesta de alimentos de origen animal como huevo; leche; carnes rojas y de aves; pescados y mariscos. Su indicación clínica es el tratamiento de la hipovitaminosis B12 administrada por vía oral o intramuscular en forma de hidroxicobalamina. La hipovitaminosis B12 se origina, principalmente, por un déficit de aporte en la dieta (malnutrición, sujetos vegetarianos o veganos, ancianos, embarazo, alcoholismo); cuando está disminuida su absorción intestinal (gastritis atrófica, síndrome de malabsorción intestinal, cirugía gastro-intestinal) y asociada a ingesta de fármacos (antiácidos, metformina). La hipervitaminosis B12 se ha relacionado con la insuficiencia renal; hepatopatías como cirrosis y hepatitis en fase aguda; alcoholismo con o sin afectación hepática; tumores sólidos de pulmón, hígado, esófago, páncreas y colorrectal y en neoplasias hematológicas como leucemia y la displasia medular." ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2195 "Ancho" => 3349 "Tamanyo" => 408925 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Schematic representation of the metabolism and elimination of vitamin B12. Anti-H2: type 2 histamine receptor antagonists; IF: intrinsic factor; HCl: hydrochloric acid; PPI: proton pump inhibitors; RDI: recommended daily intake; IM: intramuscular; SC: subcutaneous; TCII: transcobalamin II; Vit. B12: vitamin B12." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Anti-H2: type 2 histamine receptor antagonists; PPI: proton pump inhibitors." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Related to a deficit of vitamin B12 in the diet or intake \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vegan or strict vegetarian diets, pregnant people, older adults, individuals with chronic alcohol use disorders, newborns of mothers with vitamin B12 deficiency. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Related to abnormalities in intestinal absorption of vitamin B12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Atrophic gastritis (related to Helicobacter pylori or not); pernicious anemia; gastrointestinal surgery: bariatric, gastrectomy, blind loop syndrome, bypass, ileum resection; celiac disease; malabsorption syndromes; ileitis (for example, Crohn’s disease); pancreatic failure; bacterial overgrowth; parasites (Dibothriocephalus latus); Imerslund-Gräsbeck syndrome. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Related to the intake of drugs which impede or hinder vitamin B12 absorption \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Metformin, antacids such as PPI (omeprazole, etc.) and anti-H2 (famotidine, etc.), colchicine, aminosalicylates, cholestyramine, neomycin. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Related to cellular metabolism of vitamin B12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hereditary deficit of transcobalamin 2. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3333166.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Causes of vitamin B12 deficiency." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:34 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epidemiología de la dermatitis de contacto: prevalencia de sensibilización a diferentes alérgenos y factores asociados [Epidemiology of contact dermatitis: prevalence of sensitization to different allergens and associated factors]" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M.T. 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