Symptoms of vitamin B12 deficiency

There are hereditary and acquired forms of vitamin _B12 deficiency anemia.

Hereditary forms of vitamin B ₁₂ deficiency anemia

They are rare. Clinically, they are characterized by a typical picture of megaloblastic anemia with symptoms of damage to the gastrointestinal tract and nervous system.

Causes of congenital (hereditary) forms of vitamin B ₁₂ deficiency anemia

1. _{Vitamin B12} absorption disorder
   1. Insufficient secretion of intrinsic factor:
      1. congenital intrinsic factor deficiency
         1. quantitative
         2. qualitative
      2. juvenile psoriatic anemia (autoimmune)
      3. juvenile pericardial anemia (antibodies against gastric mucosa) with autoimmune polyendocrinopathy
      4. juvenile pernicious anemia with IgA deficiency
   2. Insufficient absorption in the small intestine (selective malabsorption of vitamin B ₁₂ ).
      1. abnormal intrinsic factor
      2. disruption of cobalamin transport to enterocytes (Imerslund-Gresbeck syndrome)
2. _{Vitamin B12} transport disorder
   1. Congenital transcobalamin II deficiency
   2. Transient transcobalamin II deficiency
   3. Partial transcobalamin I deficiency
3. _{Vitamin B12} metabolism disorder
   1. Adenosylcobalamin deficiency: cobalamin A and B diseases
   2. Methylmalonyl-CoA mutase deficiency (mut°, mut~)
   3. Combined adenosylcobalamin and methylcobalamin deficiency: cobalamin diseases C, D and F
   4. Methylcobalamin deficiency: cobalamin E and G diseases.

_{Vitamin B12} absorption disorder

The diseases are inherited in an autosomal recessive manner, consanguineous marriages are common. It has been established that the human intrinsic factor gene is localized on chromosome It; the locus of Imerslund-Gräsbeck syndrome is located on chromosome 10. Symptoms of the disease usually appear gradually. Children experience lethargy or irritability, anxiety; decreased appetite up to anorexia; slow weight gain, delayed physical development. Nausea, vomiting, and diarrhea are possible. The pallor of the skin and mucous membranes gradually increases, subictericity appears. Aphthous stomatitis, glossitis, and hepatosplenomegaly are characteristic. Neurological disorders are typical - hyporeflexia, the appearance of pathological reflexes, ataxia, speech defects, paresthesia, and the development of clonus and coma are possible. Laboratory tests in patients have a reduced concentration of vitamin B ₁₂ in the blood serum, methylmalonic aciduria is noted. Treatment is carried out by parenteral administration of large doses of vitamin B ₁₂ (1000 mcg intramuscularly daily for at least 2 weeks); after normalization of the clinical and hematological picture of the disease, maintenance therapy with vitamin B ₁₂ is carried out throughout life (1000 mcg intramuscularly once a month). Patients with hereditary deficiency of HF, in addition to parenteral administration of vitamin B ₁₂, are prescribed replacement therapy with human intrinsic factor.

_{Vitamin B12} transport disorder

Congenital transcobalamin II deficiency (TC II)

TC is the main transport vehicle for vitamin B ₁₂, its congenital deficiency is inherited autosomal recessively and is accompanied by impaired absorption and transport of the vitamin. Clinical manifestations of the disease are noted at the age of 3-5 weeks and are characterized by the appearance of lethargy, decreased appetite, slow weight gain with the development of hypotrophy, vomiting, diarrhea may be; recurrent infections are observed due to immune deficiency of both cellular and humoral types; later, damage to the nervous system appears. Progressive pancytopenia is noted in the peripheral blood - pronounced megaloblastic anemia with neutropenia, thrombocytopenia. The level of cobalamin in the blood serum is usually normal. Homocystinuria and methylmalonic aciduria are noted. To diagnose TK II deficiency, ion exchange chromatography or serum electrophoresis on polyacrylamide gel labeled with "Co B _12" is used. Since TK II is synthesized by amniocytes, prenatal diagnosis of TK II deficiency is possible.

Hereditary vitamin _B12 deficiency anemias caused by impaired absorption of the vitamin

Signs	Form of the disease
	Hereditary deficiency of intrinsic factor (congenital pernicious anemia)	Juvenile pernicious anemia (autoimmune)	Juvenile pernicious anemia with autoimmune polyendocrinopathies or selective IgA deficiency	Imerslund-Graesbeck syndrome (essential epithelialization with megaloblastic anemia syndrome)
Reason for development	Congenital absence of HF synthesis or congenital defects in the HF molecule	Presence of antibodies that block the secretion of HF by the gastric mucosa	Presence of antibodies that block the secretion of HF by the gastric mucosa	Impaired transport of the VF-B 12 complex to enterocytes due to the absence of receptors for the VF-B 12 complex
Timing of onset of symptoms	The first 2 years of life, sometimes in adolescents and adults	9 months - 5 years (time of depletion of vitamin B 12 reserves acquired by the fetus in utero)	10 years and older	The first 2 years of life, sometimes later
Histology of the gastric mucosa	The mucous membrane is unchanged.	Atrophy of the mucous membrane	Atrophy of the mucous membrane	The mucous membrane is unchanged.

Treatment: 1000 mcg of vitamin B ₁₂ intramuscularly 2 times a week. After normalization of the clinical and hematological picture of the disease, maintenance therapy is carried out - 250-1000 mcg of vitamin B ₁₂ monthly throughout life.

Partial transcobalamin I (TK I) deficiency

Partial deficiency of TK I (also known as "R-binder" or haptocorrin) has been described. The concentration of vitamin B ₁₂ in the blood serum of such patients is very low, but there are no clinical and hematological signs of vitamin B ₁₂ deficiency, since patients have normal levels of TK I. The concentration of TK I is 2.5 - 5.4% of the norm. Clinically, the disease manifests itself as myelopathy, which cannot be explained by other causes.

_{Vitamin B12} Metabolism Disorders

Cobalamin is a cofactor of two intracellular enzymes: methylmalonyl-CoA mutase and homocysteine-methionine methyltransferase (methionine synthetase).

Methylmalonyl-CoA mutase is a mitochondrial enzyme that dissimilates methionine and other amino acids - valine, isoleucine, threonine at the stage of isomerization of methylmalonyl-CoA to succinyl-CoA. With vitamin B ₁₂ deficiency, the activity of methylmalonyl-CoA mutase decreases, which leads to disruption of the propionate pathway of amino acid metabolism. The intermediate metabolite - methylmalonate - is excreted from the body without being converted to succinyl-CoA and, therefore, without entering the Krebs cycle, which is associated with the metabolism of amino acids, carbohydrates, lipids.

Methionine synthetase catalyzes the transfer of methyl groups from N-methyltetrahydrofolate to homocysteine to form methionine; it simultaneously maintains the folate system in an active state, which carries out the transfer of one-carbon compounds in the metabolism of histidine, the biosynthesis of purines, thymidine, and, accordingly, in the synthesis of nucleic acids. With a deficiency of vitamin B ₁₂, the resynthesis of methionine by this system ceases, and folic acid accumulates in the form of methyltetrahydrofolate, which is not used in other reactions. This enzyme is contained in actively proliferating cells of the bone marrow and epithelium.

Decreased methylmalonyl-CoA mutase activity is accompanied by increased excretion of methylmalonic acid. Decreased methionine synthetase activity leads to hyperhomocysteinemia and homocystinuria. Methylmalonic aciduria is characterized by severe metabolic acidosis with accumulation of large amounts of acids in the blood, urine, and cerebrospinal fluid. The incidence is 1:6 1,000.

All disorders of cobalamin metabolism are inherited in an autosomal recessive manner; they differ in clinical manifestations; their prenatal diagnosis is possible. Defects of cobalamins A, B, C, E and F in the fetus are determined using fibroblast culture or biochemically in amniotic fluid or maternal urine. In some cases, cobalamin administration in utero is successful.

Adenosylcobalamin deficiency: cobalamin A and B diseases.

Adenosylcobalamin is not synthesized in the cells of patients, which causes the development of methylmalonic aciduria without homocystinuria. In the first weeks or months of life, patients develop severe metabolic acidosis, leading to developmental delays in the child. Hypoglycemia and hyperglycinemia are noted. The concentration of vitamin B ₁₂ in the blood serum is normal, megaloblastic anemia is absent.

Treatment: hydroxycobalamin or cyanocobalamin 1,000-2,000 mcg intramuscularly 2 times a week for life.

Methylmalonyl-CoA mutase deficiency

There are 2 types of enzyme deficiency:

• mut" - enzyme activity is not determined;
• mutr is a residual enzyme activity that can be stimulated by high doses of cobalamin. Methylmalonic aciduria occurs, causing severe metabolic acidosis. Clinically, repeated vomiting leading to exsicosis, muscle hypotonia, apathy, and developmental delays are noted. The level of ketones, glycine, and ammonium in the blood and urine is elevated. Many patients experience hypoglycemia, leukopenia, and thrombocytopenia. Treatment: limit the amount of protein in the diet (exclude the intake of amino acids - valine, isoleucine, methionine, and threonine). Carnitine is prescribed to those patients who have a deficiency. Lincomycin and metronidazole are prescribed to reduce the production of propionate in the intestine by anaerobic bacteria. Despite therapy, patients may develop complications: basal ganglia infarction, tubulointerstitial nephritis, acute pancreatitis, cardiomyopathy.

Combined adenosylcobalamin and methylcobalamin deficiency: cobalamin diseases C, D, and F

Patients do not synthesize either methylcobalamin (which leads to homocystinuria and hypomethioninemia) or adenosylcobalamin (which leads to methylmalonic aciduria), which causes a deficiency in the activity of methylmalonyl-CoA mutase and methionine synthetase. The disease begins in the first years of life. Clinically, there is megaloblastic anemia, delayed physical development, mental retardation, apathy, possible seizures, delirium. Hydrocephalus, pulmonary heart disease, liver failure, pigment retinopathy are noted. Patients with early onset of the disease may die in the first months of life, with a late onset of the disease, the prognosis is more favorable. Treatment: large doses of vitamin B ₁₂ (1,000-2,000 mcg) intramuscularly 2 times a week constantly.

Methylcobalamin synthesis deficiency: cobalamin diseases E and G

Impaired methylcobalamin synthesis results in decreased methionine synthetase activity, which causes the development of homocystinuria and hypomethioninemia, usually without methylmalonic aciduria, although transient methylmalonic aciduria may be observed in cobalamin E disease. The disease begins in the first two years of life, sometimes in adults. Clinically, megaloblastic anemia, developmental delay, neurological disorders, nystagmus, hypotension or hypertension, stroke, blindness, and ataxia are noted. Treatment: hydroxycobalamin 1,000-2,000 mcg parenterally 1-2 times a week. Prenatal diagnosis of cobalamin E disease is possible; if the diagnosis is confirmed, the mother is prescribed vitamin B ₁₂ parenterally 2 times a week from the second trimester of pregnancy.

Acquired forms of vitamin _B12 deficiency anemia

They are much more common than hereditary ones.

Causes of acquired vitamin _B12 deficiency anemia:

Inadequate intake of vitamin B ₁₂.

1. _{Vitamin B12} deficiency in the mother (vegetarianism, pernicious anemia, sprue), leading to vitamin B12 deficiency _in breast milk - megaloblastic anemia in breastfed children develops at 7-24 months (sometimes at an earlier age).
2. Alimentary deficiency of vitamin B ₁₂ (dietary content < 2 mg/day).
   1. strict vegetarianism (complete absence of milk, eggs, and meat products in the diet);
   2. starvation;
   3. fast food;
   4. in young children when fed goat's milk or diluted dry cow's milk.

_{Vitamin B12} absorption disorder

1. 1. Insufficiency of intrinsic factor secretion:
   1. pernicious anemia (antibodies against the gastric mucosa);
   2. diseases of the gastric mucosa;
   3. erosive lesions;
   4. partial or total gastrectomy.
2. Insufficient absorption in the small intestine:
   1. specific malabsorption of vitamin B ₁₂ - the use of chelates (phytates, EDTA) that bind calcium, which leads to impaired absorption of vitamin B ₁₂;
   2. intestinal diseases accompanied by generalized malabsorption, including malabsorption of vitamin _B12;
   3. diseases of the terminal ileum (resection, bypass, Crohn's disease, tuberculosis, lymphoma);
   4. pancreatic insufficiency;
   5. Zollinger-Ellison syndrome;
   6. celiac disease;
   7. sprue;
   8. intestinal scleroderma.
3. Competition for Vitamin B ₁₂:
   1. "blind gut" syndrome - anatomical changes in the small intestine (diverticula, anastomoses and fistulas, blind loops and pockets, strictures) lead to impaired absorption of vitamin B ₁₂ due to changes in the bacterial intestinal flora;
   2. Infestation by broad tapeworm (Diphyllobothrium latum) - the helminth competes with the host for vitamin B ₁₂, the latter can be contained in the body of the helminth in quantities necessary to achieve therapeutic remission.

Acquired disorders of vitamin B ₁₂ metabolism.

1. Increased utilization of vitamin B ₁₂:
   1. liver disease;
   2. malignant neoplasms;
   3. hypothyroidism;
   4. protein deficiency (kvashiOrkor, marasmus).
2. Taking medications that impair the absorption and/or utilization of vitamin B ₁₂ (PAS, neomycin, colchicine, ethanol, metformin, cimetidine, oral contraceptives (?), nitrous oxide.

Symptoms of the disease appear gradually. Initially, loss of appetite, aversion to meat are noted, dyspeptic phenomena are possible. The most pronounced anemic syndrome is pallor, slight icterus of the skin with a lemon-yellow tint, subicterus of the sclera, weakness, malaise, fatigue, dizziness, tachycardia, shortness of breath even with little physical exertion. Changes in the gastrointestinal tract are characteristic - glossitis (the appearance of bright red areas of inflammation on the tongue, sensitive to food intake, especially sour), accompanied by pain and burning, and the appearance of aphthae on the tongue is possible. As the inflammatory phenomena subside, the papillae of the tongue atrophy, the tongue becomes shiny and smooth - "varnished tongue". Changes in the nervous system are minimal, funicular myelosis is not observed in children. Paresthesia is most often noted - a sensation of crawling ants, numbness of the limbs, etc. Moderate hepatosplenomegaly is possible. Sometimes, with increased hemolysis, subfebrile temperature is observed. Functional changes in the gastrointestinal tract and heart are possible. Patients often experience a sharp decrease in gastric secretion. Due to prolonged hypoxia, functional myocardial insufficiency may develop (there is a disruption in the nutrition of the heart muscle, its fatty infiltration).

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