Vitamin B12 deficiency anemia: clinical guidelines

List of Abbreviations

B12 – vitamin B12, cyanocobalamin

MCV – mean corpuscular volume

MCH – mean corpuscular hemoglobin

MCHC – mean corpuscular hemoglobin concentration

LDH – lactate dehydrogenase

ECG – electrocardiogram

ALT – alanine aminotransferase

AST – aspartate aminotransferase

Ultrasound – ultrasound examination

TIBC – total iron-binding capacity

TSAT – transferrin saturation

MMA – methylmalonic acid

Terms and Definitions

Vitamin B12-deficiency anemia – a macrocytic anemia caused by vitamin B12 deficiency, whose distinctive morphological features are erythrocyte hyperchromia and megaloblastic erythropoiesis; it is also characterized by morphological abnormalities of other hematopoietic lineages in the bone marrow, cytopenias, and neutrophil nuclear hypersegmentation in the blood, along with the frequent development of psychoneurological symptoms (funicular myelosis).

Cobalamin – the biochemical name for vitamin B12.

Castle's intrinsic factor – a protein produced by the parietal cells of the body and fundus of the stomach (discovered by W. Castle in 1930), required for the absorption of vitamin B12.

Cubilin - a specific receptor protein required for binding the vitamin B12-Castle's intrinsic factor complex, ensuring the uptake of this complex into the ileal wall.

Methylmalonic acid (MMA) – a substrate for the methylmalonyl-CoA enzyme, for which vitamin B12 serves as a cofactor.

Funicular myelosis - a complex of neurological disorders (paresthesias, hyporeflexia, Babinski sign) characteristic of vitamin B12 deficiency.

Reticulocyte crisis – an increase in reticulocyte count by more than 20–25% from baseline.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Vitamin B12-deficiency anemia (megaloblastic anemia, pernicious anemia, Addison-Biermer disease) is characterized by progressive hyperchromic macrocytic anemia, neutrophil nuclear hypersegmentation, megaloblastic erythropoiesis, and morphological abnormalities of other hematopoietic lineages in the bone marrow; unlike other anemias, vitamin B12-deficiency anemia is frequently associated with the development of psychoneurological symptoms (funicular myelosis) [1–4].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Vitamin B12 deficiency leads to impaired thymidine synthesis and fatty acid metabolism, which in turn results in impaired DNA synthesis, accumulation of methylmalonic acid (a metabolite toxic to nerve cells), and a decrease in myelin content within nerve fibers. Clinical manifestations of B12 deficiency include numerous disorders in the hematopoietic, nervous, and endocrine systems, atrophy of the gastrointestinal mucosa, and the development of the typical clinical picture of funicular myelosis.

The primary cause of vitamin B12 deficiency development is impaired intestinal absorption. Parietal cells of the body and fundus of the stomach secrete a protein known as Castle's intrinsic factor (discovered by W. Castle in 1930), which is necessary for the absorption of vitamin B12 (cobalamin, "extrinsic factor"). Formation of the stable "cobalamin - Castle's intrinsic factor" complex begins in the alkaline environment of the duodenum; subsequently, vitamin B12 absorption takes place in the small intestine, primarily in the ileum, where cubilin, a specific receptor protein for the intrinsic factor, is located. During absorption, the complex dissociates, and vitamin B12 crosses the small intestinal wall into the bloodstream, where it binds to transcobalamin, which delivers it to target cells, including those of the bone marrow and liver.

The following pathological processes can lead to impaired vitamin B12 absorption:

- decreased production or absence of intrinsic factor due to autoantibodies against it or gastric parietal cells, other atrophic gastritides, gastric resection;

- small intestine diseases (chronic enteritis with malabsorption syndrome, tumors including lymphomas);

- competitive uptake (diverticulosis with altered flora, diphyllobothriasis, blind loop syndrome in small bowel anastomosis);

- pancreatic diseases contributing to increased acidity of the intestinal contents (gastrin-producing tumor, Zollinger-Ellison syndrome);

- long-term use of certain medications (proton pump inhibitors [ATC group A02BC], metformin**, etc.) [5,6]

Dietary vitamin B12 deficiency may develop in individuals following a vegetarian or vegan diet. All of the above risk factors for cobalamin deficiency must be considered in patients with hereditary forms of hemolytic anemia.

In children, the main causes of B12 deficiency are:

- decreased dietary intake of vitamin B12 (in infants whose mothers have a vitamin B12 deficiency or follow a strict vegetarian diet [2,7]

- impaired absorption (intrinsic factor deficiency, gastric resection, impaired ileal absorption due to congenital small bowel diseases, bowel resection)

- increased intestinal loss of cyanocobalamin (helminthiasis, blind loop syndrome)

- congenital genetic defects leading to impaired vitamin B12 transport [8–10]

1.3 Epidemiology of the Disease or Condition

B12 deficiency anemia is one of the most common anemias, the incidence of which varies across different age groups: after 60 years of age, vitamin B12 deficiency is detected in 1 in 50 individuals, and after 70 years, in 1 out of 15. Accordingly, in some countries, serum vitamin B12 concentration is measured in elderly individuals as part of routine health screenings [8–12].

1.4 Features of Coding the Disease or Condition

D51.0 Vitamin B12 deficiency anemia due to intrinsic factor deficiency

D51.1 Vitamin B12 deficiency anemia due to selective vitamin B12 malabsorption with proteinuria

D51.3 Other dietary vitamin B12 deficiency anemias

D51.8 Other vitamin B12 deficiency anemias

D51.9 Vitamin B12 deficiency anemia, unspecified

D53.1 Other megaloblastic anemias not elsewhere classified

1.5 Classification of the disease or condition

B12 deficiency anemias are classified into:

• acquired

• hereditary (congenital)

Among acquired B12 deficiency anemias, a primary form caused by autoantibodies to intrinsic factor (pernicious anemia) is distinguished, alongside secondary forms associated with one or more risk factors for B12 deficiency, such as concurrent hereditary hemolytic anemia and a strict vegan diet. The primary form, due to the autoimmune nature of B12 deficiency, often complicates the course of autoimmune thyroiditis and type 1 diabetes mellitus. Hereditary forms of B12 deficiency have been described in children with congenital genetic defects leading to impaired vitamin B12 transport [3,4,13–16].

1.6 Clinical presentation of the disease or condition

The main clinical manifestations of B12 deficiency anemia include gradually progressive weakness, apathy, exercise intolerance, palpitations, cardiac pain, dyspeptic disorders, as well as lower limb weakness, paresthesias, migratory pain, numbness of the extremities, and progressive loss of sensation in the fingers. Typical features include a bloated face and expressionless facies, pale-jaundiced skin, smooth lingual papillae ("raspberry glossy tongue"). In young individuals, premature graying of the hair is common. Low-grade fever and splenomegaly are frequently observed, which often lead to diagnostic errors. In the absence of timely diagnosis and treatment of B12 deficiency, impairment of superficial and deep proprioceptive sensation, hearing and vision loss, and areflexia develop; in advanced cases, pelvic organ dysfunction and pronounced cognitive impairment occur. In severe cases of B12 deficiency, peripheral nervous system involvement (funicular myelosis) predominates: ataxia, hyporeflexia, and the appearance of pathological signs such as the Babinski reflex [1–4,17]

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria: clinical and hematological picture of the disease and the presence of laboratory criteria for B12 deficiency.

B12 deficiency anemia is characterized by a combination of hematological disorders with gastrointestinal pathology and symptoms of nervous system damage.

Despite the significant variability of clinical manifestations of cobalamin deficiency, a comprehensive analysis of anamnestic data and clinical symptoms makes it possible to suspect the diagnosis of B12 deficiency anemia and minimizes the selection of laboratory tests required to verify the diagnosis.

2.1 Complaints and Anamnesis

See the "Clinical Presentation" section

2.2 Physical Examination

See the "Clinical Presentation" section

2.3 Laboratory Diagnostics

The main laboratory criteria for diagnosing B12 deficiency anemia are:

• In the complete blood count (CBC):

• hyperchromia, macrocytosis, anisopoikilocytosis;

• neutrophil hypersegmentation;

• erythropenia and absolute reticulocytopenia

• In the general biochemical blood test:

• high LDH activity;

• moderate increase in unconjugated bilirubin;

• low blood vitamin B12 level;

• normal serum folic acid level;

• In the bone marrow aspirate:

• megaloblastic hematopoiesis;

• presence of giant myelocytes, metamyelocytes, and band neutrophils.

Differential diagnosis of B12 deficiency anemia is carried out with other types of macrocytic anemias associated with:

- folic acid deficiency;

- vitamin B₆ deficiency;

- certain forms of latent hemolysis, in which macrocytosis is due to an increased reticulocyte count in circulation;

- myelodysplastic syndromes;

- aplastic anemia.

Comments: in B12 deficiency anemia, the complete blood count (CBC) reveals macrocytic, hyperchromic anemia with an increase in mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and pronounced anisopoikilocytosis. MCHC remains within reference ranges. Characteristic changes in the complete blood count include basophilic stippling of erythrocytes, Jolly bodies and Cabot rings in erythrocytes, the presence of ovalocytes, and isolated normoblasts. The absolute reticulocyte count is decreased, while their relative count may be normal or increased. When technically feasible, the determination of reticulocyte indices can provide additional information: there is an increase in mean reticulocyte volume (macroreticulocytes), mean reticulocyte hemoglobin content, and often an elevated immature reticulocyte fraction. An early sign of B12 deficiency is neutrophil hypersegmentation, sometimes neutropenia. Moderate thrombocytopenia is frequently observed, rarely deep, usually without hemorrhagic syndrome [19, 20].

Comments: the general biochemical blood test shows a characteristic, sharp increase in LDH activity and hyperbilirubinemia—unconjugated in the initial stage, and due to both fractions in severe anemia.

Comments: in vitamin B12-deficiency anemia, serum iron and ferritin levels are typically high. However, patients with malabsorption syndrome may present with concurrent cobalamin and iron deficiency. In such cases, the typical laboratory picture of vitamin B12-deficiency anemia may be masked, hindering timely diagnosis and delaying pathogenetic therapy. Under these circumstances, the clinical presentation, medical history, and other diagnostic markers (MMA, holotranscobalamin) gain increased diagnostic significance [1–4,21].

Comments: Serum vitamin B12 levels are typically significantly reduced. Serum folate levels are normal or elevated, although a combination of both vitamin deficiencies may also occur.

If serum vitamin B12 and folate levels are within the normal range, it is advisable to determine serum holotranscobalamin (active B12), the level of which is reduced in vitamin B12 deficiency.

Comments: characteristic diagnostic features of vitamin B12-deficiency anemia include bone marrow hypercellularity and an abundance of megaloblasts, which often have bizarre nuclear shapes. Typical morphological features also include giant metamyelocytes, myelocytes, band neutrophils (granulocytes), as well as neutrophil hypersegmentation.

Comments: in patients with low vitamin B12 levels, geriatric syndromes, including frailty, [30]and cognitive disorders [30]develop more often, and functional decline is observed 60% more often [29]. Low vitamin B12 levels are also associated with low muscle strength and muscle mass [31], and low bone mineral density [32].

2.4 Instrumental Diagnostics

The identification of vitamin B12-deficiency anemia requires a standard set of instrumental examinations to determine the underlying cause of the anemia. Artificial intelligence technologies may be used to interpret the studies (if available and adapted for the diagnosis of vitamin B12-deficiency anemia).

• Esophagogastroduodenoscopy and videocolonoscopy to identify gastrointestinal pathology as the cause of impaired vitamin B12 absorption, and to rule out gastrointestinal malignancies in patients with pernicious anemia [34–37].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• Complex abdominal ultrasound (for all patients), thyroid and parathyroid ultrasound (for patients over 18 years of age) to detect changes characteristic of vitamin B12 deficiency (specifically, moderate hepatosplenomegaly as a manifestation of extramedullary hematopoiesis), as well as to diagnose comorbidities associated with vitamin B12 deficiency [1, 2, 38–40].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• Electrocardiography to diagnose cardiac arrhythmias and intracardiac conduction disturbances associated with vitamin B12-deficiency anemia [41, 42].

For patients over 18 years of age – Strength of recommendation C (Level of evidence – 4)

For patients under 18 years of age – Strength of recommendation B (Level of evidence – 3)

Comments: thyroid pathology, primarily autoimmune thyroiditis, is a pre-existing or comorbid condition in vitamin B12-deficiency anemia or latent vitamin B12 deficiency detected by serum B12 concentration measurement.

2.5 Other Procedures

Comments: when evaluating elderly patients, one should consider neuropsychiatric complaints and cognitive impairments that may precede the development of anemic syndrome [17].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

The daily requirement for vitamin B12 is 2.4 mcg. Most patients with vitamin B12 deficiency presenting with megaloblastic anemia and/or neurological symptoms (funicular myelosis) have malabsorption syndrome and require urgent parenteral administration of cyanocobalamin** (vitamin B12). Failure to provide timely replacement therapy can lead to irreversible multiorgan failure [43].

Comments: the key to correct and timely diagnosis of vitamin B12-deficiency anemia is the analysis of laboratory parameters necessary to verify cobalamin deficiency prior to prescribing cyanocobalamin**, including multivitamin preparations combined with minerals (ATX group A11AA), multivitamins (ATX group A11B), vitamin B1 in combination with vitamins B6 and/or B12 (ATX group A11DB), and vitamin B complex preparations, including combinations with other agents (ATX group A11E). This is because even a single injection of cyanocobalamin** leads to the disappearance of diagnostically significant morphological abnormalities in erythroid cells.

Comments: only a small fraction (up to 10%) of parenterally administered cyanocobalamin** binds to transcobalamin and is assimilated by cells; excess drug is excreted in the urine [44]. In vitamin B12-deficiency anemia, the daily dose of cyanocobalamin** ranges from 100–200 to 1000 mcg/day.

In the event of drug-induced allergic dermatitis, administration of cyanocobalamin** is combined with glucocorticoids (ATC group H02AB) and systemic antihistamines (ATC group R06A) [47,48]. During repeat administrations of the drug, undesirable allergic reactions can be avoided by reducing the dose of cyanocobalamin** to 100–200 mcg/day, which does not reduce therapeutic efficacy [1–4].

The duration of therapy with cyanocobalamin** is determined by the severity of vitamin B12-deficiency anemia. Following the resolution of anemia, leukopenia, thrombocytopenia, and all morphological erythrocyte abnormalities, the course of treatment with cyanocobalamin** is continued for another 10–14 days in order to build up vitamin B12 «stores» in the liver [1–4].

The use of oral vitamin B12 preparations (cyanocobalamin and its analogs) at a dose of 1000 mcg/day has demonstrated comparable efficacy to parenteral forms in increasing serum cobalamin levels, hemoglobin concentration, and reversing neurological manifestations [4,45,49] . Oral vitamin B12 preparations (cyanocobalamin and its analogs) offer advantages such as independence from medical personnel performing injections during treatment and the absence of injection-related complications—particularly in patients receiving antithrombotic therapy, which is of special importance for elderly and senile patients.

3.2 Diagnostics at the treatment stage

Comments: signs of patient improvement in the form of reduced anemic symptoms appear after the first 3–5 injections of cyanocobalamin**. An increase in hemoglobin levels is achieved within 7–10 days, and the recovery of other hematological parameters occurs within 3–5 weeks. The adequacy of therapy can be assessed by the normalization of blood lactate dehydrogenase activity, the development of a reticulocyte crisis on days 5–7 of treatment, and changes in reticulocyte indices that precede the development of the reticulocyte crisis. Following the initiation of therapy, the mean corpuscular volume and hemoglobin content in reticulocytes rapidly decrease, while the immature reticulocyte fraction sharply increases, reflecting treatment efficacy. Upon completion of the course of cyanocobalamin** treatment, a comprehensive complete blood count including reticulocytes and, where possible, reticulocyte indices must be monitored every 3–4 months. Additional information on treatment efficacy can be provided by favorable dynamics in serum iron metabolism parameters (decrease or normalization of serum ferritin and serum iron levels) and, where possible, homocysteine (normalization of the value) [1–4].

3.3 Other Treatment

Comments: patients with megaloblastic anemia are invariably poorly adapted to anemia, as metabolic disorders affect not only hematopoiesis but also all organs and systems where cellular dystrophy occurs (due to impaired DNA synthesis). Accordingly, the decision to administer replacement therapy with red blood cell components is made on an individual basis. Elderly and senile patients often require blood component therapy even with a moderate decrease in hemoglobin (down to 75–85 g/L).

In many patients, treatment with cyanocobalamin** and the activation of erythropoiesis may reveal iron deficiency, which impedes the complete normalization of red blood cell parameters and requires standard iron supplementation therapy [21].

3.4 Medical nutritional therapy

Therapeutic medical nutrition for patients with vitamin B12-deficiency anemia during inpatient treatment in medical organizations is organized in accordance with current orders of the Russian Ministry of Health, taking into account the somatic status and comorbidity of the patient, as well as the presence and severity of cytopenia.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

There are no specific rehabilitation measures for patients with vitamin B12-deficiency anemia.

5. Prevention and Dispensary Observation

Dispenser observation (follow-up) is carried out taking into account the possibility of eliminating the cause of vitamin B12 deficiency.

Risk groups for developing vitamin B12-deficiency anemia include patients with malabsorption syndrome (celiac disease, chronic inflammatory bowel diseases), a history of gastric and intestinal resection, those undergoing maintenance hemodialysis, and pregnant women following a vegetarian diet.

6. Organization of Medical Care

Indications for emergency hospitalization to a medical organization:

1) severe anemia with pronounced hypoxic manifestations and/or lack of adaptation to reduced hemoglobin levels (decompensation of anemia).

Indications for planned hospitalization in a medical organization:

1) dispensary examination, including during the initial diagnosis of moderate or severe vitamin B12-deficiency anemia.

Indications for patient discharge from a medical organization:

1) resolution of symptoms of anemia decompensation, completion of the workup to identify the cause of vitamin B12 deficiency development.

7. Additional Information

Possible causes of vitamin B12-deficiency anemia

I. Impaired absorption of vitamin B12

Acquired forms of vitamin B12 deficiency

Impaired secretion of gastromucoprotein (intrinsic factor) in the stomach:

• Atrophy of gastric mucosa parietal cells (atrophic gastritis)

• Antibodies against gastric mucosa parietal cells

• Antibodies against gastromucoprotein or the gastromucoprotein-vitamin B12 complex

• Organic lesions of the stomach and intestines (tumors, extensive polyposis), status post gastric or intestinal resection

• Organic diseases of the small intestine (sprue, ileitis, Crohn's disease)

Hereditary forms of vitamin B12 deficiency

• Intrinsic factor deficiency

• Imerslund–Gräsbeck syndrome

• Transcobalamin II deficiency and anomalies

II. Increased vitamin B12 consumption

• Pregnancy

• Overgrowth of intestinal flora in intestinal diverticulosis,

broad fish tapeworm infestation and other parasitoses

III. Decreased vitamin B12 intake

• Inadequate nutrition

• Lack of animal-derived products

When vitamin B12-deficiency anemia is suspected in pediatric practice, one should:

• pay attention to potential manifestations of malabsorption syndrome;

• take a detailed dietary history of the child and parents;

• in the case of infants, investigate the mother's diet before and during pregnancy, as well as during breastfeeding.

Children with insufficient dietary vitamin B12 are very likely to have deficiencies in other vitamins and micronutrients (including folic acid and iron). Such children should be placed under active clinical dispensary surveillance (dispanserization) after receiving the initial examination results.

Prognosis of Vitamin B12-Deficiency Anemia

Early diagnosis of vitamin B12-deficiency anemia, timely initiation of treatment, and adequate dispensary follow-up after anemia resolution ensure a favorable prognosis regardless of the patient's age.

In elderly patients with severe anemia, the prognosis may depend on the presence and nature of concomitant diseases, including cardiovascular disorders. The development of funicular myelosis significantly worsens the prognosis.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Lukina E.A., MD, Professor, Head of the Department of Orphan Diseases, National Research Center for Hematology of the Russian Ministry of Health

2. Ponomarev R.V., PhD, Head of the Sector for the Study of Non-Neoplastic Blood Diseases, National Research Center for Hematology of the Russian Ministry of Health

3. Latyshev V.D., Head of the Day Hospital for Patients with Hereditary Metabolic Diseases, National Research Center for Hematology of the Russian Ministry of Health

4. Tsvetayeva N.V., PhD, Senior Researcher, Sector for the Study of Non-Neoplastic Blood Diseases, National Research Center for Hematology of the Russian Ministry of Health

5. Dvirnyk V.N., PhD, Head of the Centralized Clinical Diagnostic Laboratory, National Research Center for Hematology of the Russian Ministry of Health

   Members of the Russian Society of Pediatric Hematologists and Oncologists:

6. Rumyantsev A.G., MD, Professor, Chief Pediatric Hematologist of the Ministry of Health of the Russian Federation, Director of the Dmitry Rogachev Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Board Member of the Union of Pediatrists of Russia, Academician of the RAMS.

7. Maschan A.A., MD, Professor, Corresponding Member of the RAS, Deputy General Director, Director of the Institute of Hematology, Immunology and Cell Technologies, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

8. Demikhov V.G. — MD, Professor, Director of the Scientific and Clinical Center of Hematology, Oncology and Immunology, Ryazan State Medical University named after Academician I.P. Pavlov of the Russian Ministry of Health, member of the RSPHO, member of the European Hematology Association (EHA).

9. Skobin V.B., PhD, Hematologist at the Scientific and Clinical Center of Hematology, Oncology and Immunology, Ryazan State Medical University named after Academician I.P. Pavlov of the Russian Ministry of Health, member of the RSPHO.

10. Zhurina O.N., PhD, Head of the Laboratory, Scientific and Clinical Center of Hematology, Oncology and Immunology, Ryazan State Medical University named after Academician I.P. Pavlov of the Russian Ministry of Health, member of the RSPHO

    Members of the Russian Scientific Medical Society of Internal Medicine (RSMSIM):

11. Martynov A.I., Academician of the RAS, MD, Professor at the Department of Hospital Therapy, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health

12. Malyavin A.G., MD, Professor at the Department of Phthisiology and Pulmonology, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health

    Members of the Federation of Laboratory Medicine

13. Lugovskaya S.A., MD, Professor at the Department of Clinical Laboratory Diagnostics, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health

    Members of the Russian Association of Gerontologists and Geriatricians

14. Tkacheva O.N., MD, PhD, Professor, Corresponding Member of the RAS, Chief Geriatrician of the Russian Ministry of Health, Director of the Russian Clinical and Research Center of Gerontology, a structural subdivision of the Pirogov Russian National Research Medical University of the Ministry of Health of Russia

15. Kotovskaya Yu.V., MD, PhD, Professor, Deputy Director for Research at the Russian Clinical and Research Center of Gerontology, a structural subdivision of the Pirogov Russian National Research Medical University of the Ministry of Health of Russia

16. Khovasova N.O., PhD, Senior Research Fellow at the Laboratory of Musculoskeletal Diseases, Associate Professor, Head of Academic Affairs at the Russian Clinical and Research Center of Gerontology, a structural subdivision of the Pirogov Russian National Research Medical University of the Ministry of Health of Russia

    Members of the Society of Neuromuscular Disease Specialists

17. Suponeva N.A., MD, PhD, Neurologist, Corresponding Member of the RAS, Chief Research Fellow at the Department of Neurorehabilitation and Physiotherapy, Research Center of Neurology; Scientific Consultant at the Center for Diseases of the Peripheral Nervous System, Research Center of Neurology; Founder and Scientific Secretary of the Society of Neuromuscular Disease Specialists

Conflict of interest: the authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. General Practitioners

2. Pediatricians

3. Hematologists

4. Neurologists

5. Gastroenterologists

6. Geriatricians

Table 1. Scale for assessing the levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

No.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Vitamin B12 deficiency may occur in adults and children due to rare conditions such as broad tapeworm infection, rare congenital disorders associated with impaired production of intrinsic factor (the protein responsible for transporting vitamin B12 from food into the bloodstream), and autoimmune conditions caused by antibodies against intrinsic factor (pernicious anemia). Other causes may include poor nutrition, a strict vegetarian diet, or surgical removal of the stomach or part of the intestine. Identifying the exact cause always requires a comprehensive individualized evaluation, which must include determining the blood concentration of vitamin B12. Vitamin B12 deficiency leads to anemia, weight loss, pallor, chronic gastritis, inflammation of the tongue (glossitis), limb weakness, and other neurological symptoms, the latter being more common in older and elderly individuals. Persistent worsening of well-being, depression, decreased performance, or—in children—poor academic performance and developmental delay require consulting a local physician for examination. A complete blood count is essential. When recognized early, vitamin B12-deficiency anemia is easily treated with cyanocobalamin. Hemoglobin levels normalize within a month after starting treatment. If the cause of vitamin B12 deficiency can be eliminated (parasitic infection, poor diet), maintenance therapy is not required. If the cause cannot be eliminated (persistent intestinal malabsorption, refusal to abandon a vegetarian diet, presence of intrinsic factor antibodies, or congenital deficiency), lifelong maintenance administration of cyanocobalamin is carried out in a patient-tailored regimen. Self-medication with the drug is strictly unacceptable. Treatment must be prescribed by a physician taking into account all indications and contraindications.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

No.