Vitamin B12 or cobalamin is one of the B vitamins essential for enzymatic reactions in our body which, as it is not synthesized by the human body, requires dietary supplementation. Its main dietary source is animal products, and there may be a lack of this vitamin in cases of food restriction or reduced absorption capacity1.
Vitamin B12 is produced by microorganisms present in the digestive tract of animals, in soil and in unsanitary vegetables, which are ingested by animals in their diet. When ingesting vitamin B12, it binds to the R-ligand that is secreted in the saliva, by the salivary glands, and in the gastric juice, forming the R-B12-ligand complex when it reaches the acidic environment of the stomach. The stomach also secretes intrinsic factor (IF), another substance produced by gastric parietal cells with an affinity for cobalamin. Upon reaching the duodenum, the R-B12 ligand complex is degraded by pancreatic enzymes and the FI-B12 complex is formed, which is then absorbed by the enterocytes in the ileum through specific receptors2.
Vitamin B12 deficiency can be caused by low intake, autoimmune diseases, altered bowel function, gastrointestinal tract surgery, genetics, pregnancy and lactation, medication use, and food-bound cobalamin malabsorption (FBCM)3. As the body's reserves are greater than the body's daily needs, this deficiency usually reaches clinical expression only after 3 to 5 years of severe supplementary deficiency4.
Among the autoimmune diseases, the best known is pernicious anemia, in which there is production of anti-parietal cell and anti-intrinsic factor autoantibodies, impairing the production of IF and its binding to cobalamin and the ileal receptor, which can also cause atrophic gastritis, due to cell destruction4. Another autoimmune condition is Sjögren's syndrome, which leads to reduced salivary gland secretion and consequent impairment of R-ligand release, among other changes in the digestive tract3,5.
Currently, the most common cause of vitamin deficiency is food-linked cobalamin malabsorption (FBCM), when the release of vitamin B12 from ingested foods is impaired due to altered gastric environment. It can be caused by abuse of the aforementioned drugs (PPIs and anti H2) and by antacids, senescence, atrophic gastritis, chronic gastritis, gastritis associated with Helicobacter pylori and achlorhydria, that is, factors that reduce the secretion of hydrochloric acid, making digestion difficult. of proteins and dissociation of vitamin B12. It is estimated that 30 to 40% of cases of subclinical deficiency occur as a result of FBCM3.
It is not possible to point out the prevalence of vitamin B12 deficiency in the Brazilian population due to the lack of studies in the general population, but in industrialized countries, it is estimated that it is 20% in the population over 60 years of age3,5−6. In the USA, the prevalence of vitamin B12 deficiency has been shown to vary according to age group, affecting approximately 6% of people aged up to 59 years and 20% of people aged 60 years and over5.
Regarding the etiology, FBCM is the most common cause of low serum cobalamin levels, however, pernicious anemia is responsible for the majority of severe cases3. Some specific populations have higher prevalence rates, such as pregnant women, women in breastfeeding and infants from developing countries7.
Vitamin B12 participates in chemical and enzymatic reactions essential for the functioning of the organism, it plays a fundamental role in neuronal health and in the formation of the myelin sheath and in the production of DNA strands necessary for the production of blood cells3.
In the laboratory, the increase in mean corpuscular volume is the earliest manifestation, and may occur with or without anemia. In addition, there may be an increase in RDW, which represents the variation in the shape and size of red blood cells1. On a peripheral blood smear, the presence of multisegmented neutrophils is a sign of megaloblastic leukopoiesis. For this change to be detected, more than 5% of neutrophils with more than 5 nuclear lobes must be visualized1–2. In the myelogram, erythrocytes may show traces of DNA (Howell-Jolly bodies) and megakaryopoiesis may be present. affected, forming giant platelets, however, resulting in varying degrees of thrombocytopenia1.
In the bone marrow, ineffective erythropoiesis occurs, in which the majority of erythroid progenitor cells die and are phagocytosed by medullary macrophages. This intramedullary cell destruction is diagnosed by elevated serum lactate dehydrogenase (LDH), low reticulocyte count, and reduced serum haptoglobin concentrations1.
Clinical manifestations can be hematological and neurological or neuropsychiatric and often do not manifest simultaneously. Sometimes, individuals may have lesions in the oral cavity, such as angular cheilitis and glossitis. The main hematological manifestations are due to anemia and its associated symptoms, due to reduced production of red blood cells. Clinically, it courses with fatigue, dyspnea, symptoms of heart failure, dizziness and pallor1.
Neurological changes may precede hematological changes and consist of symptoms of peripheral neuropathy, subacute combined spinal cord degeneration, impairment of the autonomic system and neuropsychiatric conditions. Usually, the first change is peripheral sensory impairment, most often as distal and symmetrical paresthesias in the lower limbs. Subacute combined degeneration occurs in the most severe cases and is clinically characterized by symmetrical dysesthesia, proprioception disturbance, and spastic paraparesis or tetraparesis. Few patients present with involvement of the autonomic nervous system or neuropsychiatric condition, which may present with urinary/fecal incontinence, erectile dysfunction, depressive symptoms, mania, delirium, psychosis and cognitive loss1,3. Most patients present with loss of vibratory sensitivity, impaired proprioception, reduced tactile sensitivity and alteration in the Romberg maneuver with a tendency to fall to either side1.
Delayed diagnosis and consequent delay in the treatment of vitamin B12 deficiency can result in potentially irreversible serious complications, including spinal cord degeneration and pancytopenia, so early diagnosis and appropriate treatment should be performed3. How deficiency of cobalamin at the cellular level is manifested by the accumulation of intermediary products of the metabolic pathways, in addition to the serum dosage of vitamin B12, this deficiency can be confirmed by the dosage of methylmalonic acid (AMM), by the levels of homocysteine or by the quantification of serum holotranscobalamin4,8−10.
All biochemical tests are subject to individual variation due to other conditions, and diagnostic cutoffs fluctuate excessively, which can result in asymptomatic patients with abnormal tests or cases with normal clinical manifestations and laboratory tests11. In the first case, levels falsely Low levels of cobalamin on tests can occur in folate deficiency, haptocorrin deficiency, multiple myeloma, or oral contraceptive therapy3.
Diagnostic criteria include serum cobalamin < 200 pg/mL plus one of the following: signs and symptoms; altered hematological indices; elevated serum homocysteine or increased serum AMM11. It is important to emphasize that there is no reference method or gold standard for this diagnosis, and it is essential to assess the clinical picture3,10−11. In clinical practice, the identification of anemia macrocytic cell count and findings of more than 5% of plurisegmented neutrophils on hematoscopy suggest vitamin B12 deficiency, but this must be confirmed with specific tests3.
Once the deficiency is confirmed, patients should be reassessed within 1 to 2 months and those who show improvement in the laboratory do not require further investigation. On the other hand, cases that persist with low levels should be tested for pernicious anemia and oral supplementation should be initiated with the guidance to seek medical attention in cases of neurological symptoms3.
In severe neurological cases, in pregnant women or if there is diagnostic uncertainty, referral for secondary evaluation by specialists is recommended. Patients with suspected malabsorption, gastric cancer or celiac disease should be followed up by the gastroenterology service. When the deficiency is caused by drug abuse, discontinuation of the medication is recommended3.
Currently, the most indicated route for replacement is the intramuscular parenteral route, however, studies have shown efficacy with oral replacement therapy. The advantages are patient convenience, reduced healthcare costs for administering injections, and reduced risk of bleeding and infection3. Cyanocobalamin is the most commonly used form for formulating supplements and fortifying foods due to its stability even when exposed to high temperatures. The use of multivitamins is not recommended, as cobalamin can be degraded in the presence of vitamin C and copper, forming compounds that interact with transport proteins and inhibiting the transport system for intestinal absorption11.