Definition of illness. Causes of the disease
B12-deficiency anemia (B12DA) is a disease in which the level of red blood cells and hemoglobin decreases due to a lack of vitamin B12 in the body.
Synonyms: Addison’s anemia – Birmer, megaloblastic, pernicious anemia.
Vitamin B12 is involved in the formation of all blood cells (erythrocytes, leukocytes, platelets), and cells of the gastrointestinal tract and ensures the normal functioning of the cells of the nervous system.
Therefore, with anemia associated with vitamin B12 deficiency, signs of damage to the gastrointestinal tract and nervous system are often observed, and the level of platelets and leukocytes decreases in the blood test.
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B12DA occurs in 1500 people per 1 million population, in both children and adults. However, people over the age of 60 are more commonly affected. In women, the incidence is higher than in men: the ratio is 10:7.
Causes of B12 deficiency anemia
The reasons for the development of B12DA are insufficient intake of the vitamin in the body, a violation of its release from food, a violation of absorption, transport, metabolism (metabolism), or its increased consumption. Let’s take a closer look at each reason.
1. Insufficient supply. Vitamin B12 is found only in animal products. If little or no vitamin B12 is supplied with food, for example, with vegetarianism or veganism, B12DA develops after 2-4 years. In infants, a deficiency can develop with a reduced content of B12 in breast milk due to a vitamin deficiency in the mother.
2. Violation of the release of B12 from food can be caused by the following reasons:
Loss or damage to the parietal cells of the stomach. Vitamin B12 is found in food in protein form. B12 is released from food under the influence of hydrochloric acid and protein-digesting enzymes in the stomach. Hydrochloric acid is produced by the parietal cells of the stomach. The reasons for the violation of its production may be the loss or damage of parietal cells as a result of:
Surgical intervention on the stomach: total or subtotal resection, for example, in gastric cancer.
Atrophic gastritis is a chronic inflammation of the stomach. Including autoimmune gastritis, in which the immune system mistakenly recognizes the parietal cells of the stomach as foreign and destroys them with the help of specific antibodies.
Cancer or polyposis of the stomach, which damage and displace the parietal cells of the mucous membrane.
Deficiency of pancreatic enzymes. After being released from dietary proteins, vitamin B12 binds to the saliva protein haptocorrin, which protects the vitamin from the acidic environment of the stomach. In the duodenum, B12 is released under the influence of pancreatic enzymes. Enzyme deficiencies can be caused by pancreatic insufficiency, chronic pancreatitis, or Zollinger-Ellison syndrome (pancreatic tumor).
3. Malabsorption of the vitamin in the small intestine. Possible reasons:
Castle intrinsic factor deficiency. After the release of the vitamin from saliva proteins, B12 binds to the intrinsic factor of Castle, a protein that is produced by the parietal cells of the stomach. It is only through this connection that the vitamin can be absorbed in the small intestine. Causes of deficiency of intrinsic factor Castle:
Congenital deficiency of intrinsic factor Castle is a hereditary disease characterized by a defect in the gene responsible for the formation of this factor.
Loss of parietal cells of the stomach.
Congenital and Acquired Bowel Diseases:
Imerslund-Gresbeck Syndrome is a rare hereditary disease caused by a malfunction of the cube receptor in the ileum. Vitamin B12 is absorbed through this receptor.
Celiac disease is gluten intolerance that damages the lining of the small intestine.
Crohn’s disease is a chronic inflammatory bowel disease.
Tumors of the small intestine, including lymphomas.
Resection of the ileum.
Long-term use of certain drugs: proton pump inhibitors, aminosalicylic acid, metformin, colchicine, neomycin, biguanides, cimetidine, oral contraceptives, etc.
4. Violation of transport. After absorption in the intestine, vitamin B12 enters the bloodstream, where it binds to the transporter protein transcobalamin II. It delivers the vitamin to consumer cells. A congenital defect of the transporter protein or the appearance of antibodies to it leads to a violation of the transport of vitamin B12 and its deficiency.
5. Violation of metabolism. Penetrating from the blood into cells, vitamin B12 takes part in complex biochemical processes leading to DNA synthesis, cell division and maturation, fatty acid, and homocysteine metabolism. Congenital and acquired defects in the enzymes that support these processes can lead to the development of B12DA.
6. Increased consumption of vitamin B12. It May be caused by:
Conditions associated with increased consumption: multiple pregnancies, thyrotoxicosis, oncohematological diseases (multiple myeloma, myeloproliferative diseases).
Competitive intake of the vitamin: by bacteria, such as in diverticulosis and blind loop syndrome; parasites – with diphyllobothriasis and whipworm.
Symptoms of B12 deficiency anemia
With intrinsic factor deficiency, transport protein deficiency, intracellular metabolism disorders, and some other congenital conditions, symptoms of B12DA may appear in children in the first months or years of life. When dietary intake is inadequate or malabsorption occurs, symptoms develop gradually, usually in children over 7 years of age and in adults.
All manifestations of B12DA can be divided into 3 groups:
symptoms associated with a decrease in hemoglobin-anemic syndrome;
symptoms of damage to the gastrointestinal tract – gastroenterological syndrome;
symptoms of damage to the nervous system – neuropsychic syndrome.
Each of these groups of symptoms can be present separately, and their combination can occur.
With B12DA, as with any anemia, pallor of the skin is observed, sometimes with an anicteric tinge. May be disturbed by general weakness, fatigue, drowsiness, and shortness of breath with little physical exertion.
Possible palpitations, tinnitus, dizziness, darkening of the eyes, flashing “flies” before the eyes. Attention is drawn to the decrease in memory, performance, and performance at school or university. In children with a background of an anemic syndrome, growth and development disorders are possible.
Symptoms of damage to the gastrointestinal tract
For patients with B12DA, a specific symptom is inflammation of the tongue, which is accompanied by discomfort and pain. At the same time, the tongue is bright red, with smoothed papillae (“varnished tongue”, Gunther’s glossitis), areas of inflammation, cracks, and ulcerations. There may be sores in the corners of the mouth and pain in the gums and lips.
Perhaps a decrease in appetite and, as a result, weight loss, a feeling of heaviness in the abdomen, diarrhea. Sometimes the liver and spleen slightly increase, which can be detected by palpation of the abdomen by a doctor or by ultrasound of the abdominal organs.
Symptoms of damage to the nervous system
Damage to the nervous system with B12DA is called funicular myelosis. It affects the posterior and lateral columns of the spinal cord, as well as peripheral nerves. More common in men. This condition is manifested by numbness, paresthesias (a crawling sensation), weakness in the legs, and impaired gait. Less often, such complaints from the hands are observed, while there is difficulty in performing precise movements.
Sometimes hearing, smell, and vision are disturbed, and mental disorders occur from irritability to severe dementia and psychosis. Neurological manifestations such as urinary incontinence and involuntary defecation may occur. In young children, symptoms of damage to the nervous system can be muscle weakness, trembling, involuntary muscle contractions. There may be a delay in psychomotor development and loss of skills.
Pathogenesis of B12 deficiency anemia
Vitamin B12 enters the body with animal products: meat products, eggs, cheese, and milk. From the connection with food proteins, the vitamin is released first under the influence of cooking, and then hydrochloric acid and gastric juice enzymes.
In the duodenum, vitamin B12 combines with the intrinsic factor Castle, which is synthesized by the parietal cells of the stomach. Thanks to the Castle factor, vitamin B12 enters the cells of the mucous membrane of the ileum. After that, it binds to the transport protein transcobalamin II and is carried by the blood to consumer cells, mainly to the liver and bone marrow.
In the cell, vitamin B12 is converted into two coenzymes: methylcobalamin and adenosylcobalamin. Coenzymes are compounds necessary for the functioning of enzymes.
Methylcobalamin is a coenzyme for the enzyme methionine synthase, which converts one amino acid, homocysteine, to another, methionine. If this process fails, homocysteine accumulates in the body, and pyrimidine bases necessary for the formation of DNA are not formed. As a result, DNA synthesis and cell division processes are disrupted. Rapidly dividing cells are especially sensitive to this change – hematopoietic cells of the bone marrow, from which blood cells are formed, as well as epithelial cells of the gastrointestinal tract. Hence the appearance of such changes in the blood test as anemia, leukopenia (decrease in the number of leukocytes), thrombocytopenia (decrease in the number of platelets), as well as atrophy of the mucous membranes.
The second coenzyme – adenosylcobalamin – is involved in the metabolism of fatty acids, which is necessary for the metabolism of myelin (a substance that forms the sheath of nerve fibers). Incorrect metabolism of fatty acids due to a lack of vitamin B12 leads to the accumulation of acids toxic to the nervous system – methylmalonic and propionic. Myelin synthesis is impaired in the posterior and lateral columns of the spinal cord. As a result, there is a clinic of damage to the nervous system.
Classification and stages of development of B12-deficiency anemia
Classification of V12DA for reasons of development:
Hereditary (congenital) forms. Described in children with genetic abnormalities that impair the transport and metabolism of vitamin B12.
the primary form is due to an autoimmune cause of vitamin B12 deficiency, that is, the presence of antibodies to the parietal cells of the stomach or the Castle factor. Often, the primary form of B12DA complicates the course of diseases such as autoimmune thyroiditis, vitiligo, or type 1 diabetes mellitus .
The secondary form occurs in the background of a strict vegan diet .
Stages of development B12YES:
Initial – latent deficiency. The level of the vitamin in the blood serum is reduced, but the number of erythrocytes and the level of hemoglobin remains normal. Clinical manifestations at this stage may not be observed. It is possible to detect a change in the parameters of erythrocytes in the laboratory: an increase in the average volume of an erythrocyte (MCV parameter in a blood test) and the average content of hemoglobin in an erythrocyte (MCH parameter).
Stage of clinical manifestations. It is observed with a decrease in hemoglobin levels, when symptoms of anemia appear, and with damage to the nervous system.
The severity of V12DA:
Mild – a decrease in hemoglobin levels to 90 g / l.
Moderate – hemoglobin level within 90-70 g/l.
Severe – hemoglobin level below 70 g / l.
Complications of B12 deficiency anemia
Growth and developmental delay in children are possible as a result of a decrease in hemoglobin with B12DA.
Heart failure. In elderly patients, anemia can worsen the course of concomitant cardiovascular pathology in the form of heart failure.
Weight loss may result from decreased appetite and gastrointestinal manifestations.
Accession of infectious complications is possible with the development of deep leukopenia (low level of leukocytes). The decrease in platelets, as a rule, is insignificant and does not lead to hemorrhagic complications.
Atherosclerosis, thrombosis. An increase in homocysteine levels due to vitamin B12 deficiency can cause atherosclerosis and the formation of blood clots. Accumulating in the body, homocysteine damages the inner wall of the arteries, which leads to ruptures of the inner lining of the vessels – the endothelium. Cholesterol and calcium settle at the site of damage – an atherosclerotic plaque is formed, as a result of which the lumen of the vessel narrows, and sometimes becomes clogged. This threatens thrombosis or rupture of the vessel.
Also described is such a severe complication of B12DA, as thrombotic microangiopathy is a disease based on damage to small vessels and the formation of blood clots in their lumen, which is accompanied by inflammation of the vascular wall. As a result, ischemia of organs and tissues may develop.
Damage to the brain and spinal cord without treatment can lead to spasticity (excessive muscle tone and involuntary movements) and paraplegia (complete paralysis of both arms or legs). With the start of treatment with B12DA, anemic syndrome and neurological manifestations quickly stop. However, in severe vitamin B12 deficiency, spinal cord injury may be irreversible.
Diagnosis of B12 deficiency anemia
An examination by a hematologist is important for the correct diagnosis of B12DA. To clarify and correct problems associated with the work of the gastrointestinal tract, you will need to consult a gastroenterologist. An examination by a neurologist may be necessary to evaluate neurological manifestations.
On examination, the doctor may pay attention to the pallor and slight yellowness of the skin, an increase in heart rate, and expansion of the boundaries of the heart. It is necessary to examine the oral cavity, especially the tongue. A neurologist can assess muscle tone and the presence of pathological reflexes.
One of the most important stages of diagnosis is the evaluation of a clinical blood test. The analysis shows:
decrease in hemoglobin – anemia;
macrocytosis – the presence in the blood of a large number of abnormally large red blood cells (macrocytes);
hyperchromic – intense staining of red blood cells caused by an increased amount of hemoglobin in the blood;
there may be a decrease in the number of leukocytes and platelets.
It is necessary to perform a blood smear, in which a morphologist can see the pathological forms of red blood cells:
ovalocytes (oval-shaped erythrocytes) and degenerative forms;
an increase in the difference in the size of erythrocytes (parameter RDW);
specific pathological inclusions such as Jolly bodies and Cabot rings;
megalocytes and megaloblasts – in severe cases.
Pathological forms of neutrophils can also occur:
neutrophils with nuclear hypersegmentation (5 or more segments);
metamyelocytes are immature neutrophilic leukocytes.
The number of young forms of erythrocytes (reticulocytes), as a rule, is reduced. If there is a laboratory opportunity, reticulocyte indices can provide additional useful information: the average volume of reticulocytes and the average content of hemoglobin in reticulocytes increase, and the fraction of immature reticulocytes increases.
In a biochemical blood test:
reduced levels of vitamin B12;
indirect bilirubin and lactate dehydrogenase may be elevated – a sign of early destruction (hemolysis) of erythrocytes in the blood and the breakdown of erythrocyte precursors in the bone marrow;
iron and ferritin levels are normal.
It is essential to evaluate folic acid levels, as clinical findings are similar for B12 and folic acid deficiency, but treatment differs. If B12DA is suspected, but vitamin B12 and folic acid levels are normal, a determination of serum holotranscobalamin (active vitamin B12) is recommended. In the case of B12 deficiency, its content is reduced. An increase in the level of homocysteine and methylmalonic acid in the blood serum can be detected.
In the general analysis of urine, persistent proteinuria can be observed – the appearance of protein in the urine. In some cases, there is an increase in the level of methylmalonic acid and homocysteine.
Additional lab tests that may help identify the cause of a vitamin B12 deficiency include:
the study of antibodies to the internal factor of Castle (IgG) and parietal cells of the stomach in the blood serum;
a study of gastric juice to identify the internal factor of Castle and antibodies to this factor (IgA, synthesized by the parietal cells of the stomach);
Schilling test – determines the activity of internal factor Castle and the absorption of vitamin B12 in the intestine;
tests for malabsorption (impaired absorption of nutrients).
Prenatal diagnosis of a genetically determined deficiency of the transcobalamin II transport protein is possible since it is synthesized by amniocytes (fetal membrane cells).
Ultrasound examination of the abdominal organs can detect slight hepatosplenomegaly – an increase in the liver and spleen.
To detect diseases of the gastrointestinal tract that can disrupt the absorption of vitamin B12, all patients with newly diagnosed B12DA are shown to perform endoscopic studies – fibro gastro duodenoscopy (FGDS) and colonoscopy. With FGDS, chronic atrophic gastritis, and duodenitis can be detected, and a decrease in gastric secretion can be observed. In the presence of pathological changes, it is mandatory to perform a biopsy of the gastric mucosa with further histological examination.
The differential diagnosis for B12-deficiency anemia, especially with a decrease in leukocytes and platelets, is carried out with such diseases of the blood system:
A myelodysplastic syndrome is a group of hematological disorders in which the bone marrow does not
produce enough of one or more types of blood cells: platelets, white blood cells, and red blood cells.
Aplastic anemia is an anemia that occurs due to insufficient production of red blood cells due to a decrease in the number of hematopoietic stem cells.
To clarify the diagnosis, it may be necessary to perform a puncture of the bone marrow and its morphological examination. In the presence of B12DA, a specialist morphologist describes in the bone marrow the characteristic changes in stem progenitor cells:
hyperplasia (growth) of the erythroid germ – the precursor stem cells from which erythrocytes are formed;
megaloblastic type of hematopoiesis, in which large cells with granular nuclei, pathological mitoses, Jolly bodies are formed;
violation of the maturation of myeloid cells and platelet precursors: giant metamyelocytes, neutrophil hypersegmentation, multinucleated megakaryocytes
Treatment of B12 deficiency anemia
In anemia associated with insufficient intake of the vitamin from food, treatment involves dietary modification in combination with intramuscular administration of vitamin B12. A diet rich in vitamin
B12 requires the consumption of animal products. Vegetables, fruits, and bread do not contain vitamin B12.
For other reasons, diet correction will be ineffective. In all cases, treatment involves the introduction of a vitamin B12 preparation according to standard schemes. Doses of the drug may vary depending on the age of the patient and the presence of neurological symptoms.
Treatment is usually done on an outpatient basis. Severe anemia (hemoglobin level less than 70 g/l) and advanced age can serve as an indication of hospitalization.
If B12DA is suspected without laboratory confirmation, it is strongly not recommended to start treatment with vitamin B12 or multivitamin complexes, since the introduction of B12 leads to the rapid disappearance of morphological cell abnormalities, which in turn makes it difficult to make a correct diagnosis. Misuse of folic acid in B12 deficiency can lead to worsening neurological symptoms.
Therefore, it is very important to start therapy only after laboratory confirmation of the diagnosis.
The first stage of therapy is saturation. It lasts 4-6 weeks and involves intramuscular administration of the drug cyanocobalamin in a therapeutic dose. In some cases, sublingual forms of vitamin B12 may be effective. Signs of improvement are observed after the first 3-5 injections of the drug.
The first laboratory sign of the effectiveness of therapy is a reticular crisis – an increase in the level of reticulocytes in the blood by 2-3 times compared with the baseline on days 4-7 from the start of therapy. Normalization of hemoglobin levels is achieved after 1-2 months, peripheral neuropathy stops more slowly.
Against the background of cyanocobalamin therapy, due to the active division of progenitor cells in the bone marrow, it is possible to add folic acid and iron deficiency, therefore, after 7-10 days from the start of vitamin B12 therapy, it is necessary to additionally prescribe folic acid, and with a decrease in ferritin levels – iron preparations.
The second stage is fixing therapy: vitamin B12 is administered at the same dose, but the frequency of administration decreases.
The third stage is maintenance therapy. It is held for life. Transfusion of erythrocyte suspension is indicated for severe anemia with signs of hypoxia and circulatory failure. With the development of neutropenia (decrease in the number of neutrophils) and the addition of infectious complications, antibiotic therapy may be required.
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Regardless of the age of the patient, with early diagnosis, timely initiation of treatment, and proper follow-up after recovery, the prognosis for B12DA is favorable. Concomitant cardiovascular diseases in elderly patients, as well as damage to the nervous system (funicular myelosis), can contribute to a worse prognosis.
Prevention of B12DA is reduced with the correction of the diet. If it is impossible to eliminate the cause of the disease (for example, when a part of the stomach is removed or if the internal factor of Castle is insufficient), prevention is reduced to regular lifelong administration of vitamin B12. A blood test should be monitored once every 3-4 months. Patients with atrophic gastritis are recommended to undergo annual EGD, as they have an increased risk of gastric neoplasms.
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