Vitamin B12 deficiency symptoms

Isolated hereditary and acquired forms of vitamin B _12- deficiency anemia.

Hereditary forms of vitamin B ₁₂ deficiency anemia

They are rare. Clinically characterized by a typical picture of megaloblastic anemia with the presence of symptoms of lesions of the gastrointestinal tract and the nervous system.

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

1. Violation of absorption of vitamin B ₁₂
   1. Insufficient secretion of internal factor:
      1. congenital deficiency of internal factors
         1. quantitative
         2. qualitative
      2. juvenile psoriatic anemia (autoimmune)
      3. juvenile periotic anemia (antibodies against the 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 internal factor
      2. violation of the transport of cobalamin to enterocytes (the Imerslund-Gresbek syndrome)
2. Violation of the transport of vitamin B ₁₂
   1. Congenital deficiency of transcobalamin II
   2. Transient deficiency of transcobalamin II
   3. Partial deficiency of transcobalamin I
3. Violation of the metabolism of vitamin B ₁₂
   1. Deficiency of adenosyl cobalamin: diseases of cobalamin A and B
   2. Deficiency of methylmalonil-CoA mutase (mut °, mut ~)
   3. Combined deficiency of adenosylcobalamin and methyl-cobalamin: diseases of cobalamin C, D and F
   4. Methylcobalamin deficiency: diseases of cobalamin E and G.

Violation of absorption of vitamin B ₁₂

Diseases are inherited autosomally-recessively, often related marriages. It is established that the gene of the internal factor of a person is localized on the chromosome It; the locus of the Imerslund-Gresbek syndrome is located on chromosome 10. Symptoms of the disease usually appear gradually. Children notice lethargy or irritability, anxiety; decreased appetite until anorexia; slowing of weight gain, lag in physical development. Possible nausea, vomiting, diarrhea. Gradually, the pallor of the skin and mucous membranes increases, subic- ticity appears. Characterized by aphthous stomatitis, glossitis, hepatosplenomegaly. Typical are neurological disorders - hyporeflexia, the appearance of pathological reflexes, ataxia, speech defects, paresthesia, possibly the development of clone and coma. The concentration of vitamin B ₁₂ in the blood serum is reduced in patients with laboratory testing, methylmalonic aciduria is noted. Treatment is carried out by parenteral administration of large doses of vitamin B ₁₂ (1000 μg intramuscularly daily for at least 2 weeks); after the 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 VF deficiency in addition to parenteral administration of vitamin B ₁₂, are prescribed replacement therapy by the human internal factor.

Violation of the transport of vitamin B ₁₂

Congenital deficiency of transcobalamin II (TC II)

TC is the main vehicle for vitamin B ₁₂, congenital insufficiency is inherited autosomally recessively and is accompanied by a violation of absorption and transport of the vitamin. Clinical manifestations of the disease are observed at the age of 3-5 weeks and are characterized by the appearance of lethargy, a decrease in appetite, a slowdown in weight gain with the development of hypotrophy, may be vomiting, diarrhea; there are recurrent infections due to immune deficiency of both cellular and humoral types; later there is a lesion of the nervous system. In peripheral blood there is progressive pancytopenia - pronounced megaloblastic anemia with neutropenia, thrombocytopenia. The level of cobalamin in the serum is usually normal. Homocystinuria and methylmalonic aciduria are noted. To diagnose the deficiency of TK II, ion exchange chromatography or serum electrophoresis on a 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 B _12- deficiency anemia, caused by a violation of vitamin absorption

Symptoms	Form of the disease
	The inherited deficiency of the internal factor (congenital pernicious anemia)	Juvenile pernicious anemia (autoimmune)	Juvenile pernicious anemia with autoimmune polyendo-crinopathy or selective IgA deficiency	Syndrome Imerslund-Gresbek (essential epithelion with a syndrome of megaloblastic anemia)
Cause of development	Congenital absence of WF synthesis or birth defects in the WF molecule	The presence of antibodies blocking the secretion of VF of the gastric mucosa	The presence of antibodies blocking the secretion of VF of the gastric mucosa	Violation of the transport of the VF-B 12 complex to enterocytes due to the absence of receptors for the VF-B 12 complex
The timing of the onset of symptoms	The first 2 years of life, sometimes in adolescents and adults	9 months - 5 years (the timing of the depletion of vitamin B 12, acquired by the fetus in utero)	10 years and over	The first 2 years of life, sometimes later
Histology of the gastric mucosa	Mucous is not changed	Mucosal atrophy	Mucosal atrophy	Mucous is not changed

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

The partial deficiency of transcobalamin I (TK I)

A partial deficiency of TK I (also known as "R-binder" or haptocorrin) is described. The concentration of vitamin B ₁₂ in the serum of these patients is very low, but the clinical and hematological signs of deficiency of vitamin B ₁₂ is not present, since patients have normal levels of TC TC I. Concentration I is 2 5 - 5 4% of normal. Clinically, the disease manifests itself in myelopathy, which can not be explained by other causes.

Metabolic disorders of vitamin B ₁₂

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

Methylmalonil-CoA mutase, a mitochondrial enzyme, dissimilates methionine and other amino acids - valine, isoleucine, threonine in the methylmalonyl-CoA isomerization step in succinyl-CoA. When vitamin B ₁₂ is deficient, the activity of methyl malonyl-CoA mutase decreases, which leads to a violation of the propionate pathway of amino acid metabolism. Intermediate metabolite - methyl malonate - is excreted from the body without converting to succinyl-CoA and, therefore, not entering the Krebs cycle, which involves the exchange of amino acids, carbohydrates, lipids.

Methionine synthetase catalyzes the movement of methyl groups from N-methyl tetrahydrofolate to homocysteine to form methionine; at the same time ensures the maintenance of the folate system in the active state, carrying out the transfer of single-carbon compounds in the exchange 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 is stopped by this system, and folic acid accumulates in the form of methyl tetrahydrofolate, which is not used in other reactions. This enzyme is found in actively proliferating cells of the bone marrow and epithelium.

Reduction of methylmalonil-CoA mutase activity is accompanied by increased excretion of methylmalonic acid. The decrease in methionine synthetase activity leads to pserhomocysteinemia and homocysteinuria. Methylmalonic aciduria is characterized by severe metabolic acidosis with the accumulation of a large number of acids in the blood, urine, liquor. The frequency is 1: 6 1 000.

All violations of the metabolism of cobalamin are inherited autosomally-recessively; differ in clinical manifestations; their prenatal diagnosis is possible. Defects of cobalamins A, B, C, E and F in the fetus are determined using a culture of fibroblasts, or biochemically in the amniotic fluid or the mother's urine. In some cases, the administration of cobalamin in utero is successful.

Deficiency of adenosylcobalamin: diseases of cobalamin A and B.

In the cells of patients, adenosylcobalamin is not synthesized, which causes the development of methylmalonic aciduria without homocystinuria. In the first weeks or months of life, patients develop severe metabolic acidosis, leading to a delay in the development of the child. There are hypoglycemia, hyperglycinemia. The concentration of vitamin B ₁₂ in the blood serum is normal, megaloblastic anemia is absent.

Treatment: hydroxy cobalamin or cyanocobalamin 1,000-2,000 μg intramuscularly 2 times a week for life.

Deficiency of methylmalonil-CoA mutase

There are 2 types of enzyme deficiency:

• mut "- the enzyme activity is not defined;
• mutr is the residual activity of the enzyme, which can be stimulated by high doses of cobalamin. There is a methylmalonic aciduria, which causes the appearance of severe metabolic acidosis. Clinically observed repeated vomiting, leading to exsicosis, muscle hypotension, apathy, developmental lag. The level of ketones, glycine, ammonium in the blood and urine is increased. Many patients have hypoglycemia, leukopenia, thrombocytopenia. Treatment: in the diet limit the amount of protein (exclude the intake of amino acids - valine, isoleucine, methionine and threonine). Carnitine is prescribed for those patients who are diagnosed with a deficiency. To reduce the production of propionate in the intestine anaerobic bacteria are prescribed lincomycin and metronidazole. Despite the therapy, patients may develop complications: heart attacks of the basal ganglia, tubulointerstitial nephritis, acute pancreatitis, cardiomyopathy.

Combined deficiency of adenosylcobalamin and methyl-cobalamin: diseases of cobalamin C, D and F

Patients do not synthesize either methylcobalamin (which leads to homocystinuria and hypomethioninemia) and adenosylcobalamin (which leads to methylmalonic aciduria), which leads to a deficiency in methylmalonil-CoA mutase and methionine synthetase activity. The disease begins in the first years of life. Clinically, megaloblastic anemia, lag in physical development, mental retardation, apathy, possible cramps, delirium. There are hydrocephalus, pulmonary heart, hepatic insufficiency, pigmentary retinopathy. Patients with an early onset of the disease may die in the first months of life, with the late onset of the disease a more favorable prognosis. Treatment: large doses of vitamin B ₁₂ (1,000-2,000 μg) intramuscularly 2 times a week are permanent.

Deficiency of methylcobalamin synthesis: cobalamin E and G

Violation of methylcobalamin synthesis leads to a decrease in the activity of methionine synthetase, which causes the development of homocystinuria and hypomethioninemia, usually without methylmalonic aciduria, although in transplantation of methylmalonic aciduria in cobalamin E disease. The disease begins in the first two years of life, sometimes in adults. Clinically, megaloblastic anemia, developmental lag, neurological disorders, nystagmus, hypotension or hypertension, stroke, blindness, ataxia are noted. Treatment: gidroksikobalamin on 1 000-2 000 mkg parenterally 1-2 times a week. Prenatal diagnosis of cobalamin E disease is possible, with confirmation of the diagnosis of the mother from the second trimester of pregnancy, vitamin B _{12 is} administered parenterally 2 times a week.

Acquired forms of vitamin B _12- deficiency anemia

They occur much more often than hereditary.

The causes of acquired vitamin B _12- deficiency anemia:

Inadequate intake of vitamin B ₁₂.

1. Deficiency of vitamin B ₁₂ in the mother (vegetarianism, pernicious anemia, sprue), which leads to a deficiency of vitamin B ₁₂ in breast milk - megaloblastic anemia in children breastfed develops in 7-24 months (sometimes at an early age).
2. Alimentary deficiency of vitamin B ₁₂ (content in the diet <2 mg / day).
   1. strict vegetarianism (complete absence of milk, eggs, meat products in the diet);
   2. starvation;
   3. fast food;
   4. in young children when fed with goat's milk or diluted with dry cow's milk.

Violation of absorption of vitamin B ₁₂

1. 1. Insufficiency of secretion of internal factor:
   1. pernicious anemia (antibodies against the gastric mucosa);
   2. diseases of the stomach mucosa;
   3. erosive lesions;
   4. partial or total gastrectomy.
2. Inadequate absorption in the small intestine:
   1. specific malabsorption of vitamin B ₁₂ - the use of chelates (phytates, EDTA), binding calcium, which leads to impaired absorption of vitamin B ₁₂;
   2. intestinal diseases that occur with generalized impairment of absorption, including malabsorption of vitamin B ₁₂;
   3. diseases of terminal ileum (resection, shunting, Crohn's disease, tuberculosis, lymphoma);
   4. pancreatic insufficiency;
   5. Zollinger-Ellison syndrome;
   6. celiac disease;
   7. sprue;
   8. intestinal scleroderma.
3. Competitive struggle for vitamin B ₁₂ :
   1. syndrome of the cecum - 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 bacterial intestinal flora;
   2. invasion by a wide ribbon (Diphyllobothrium latum) - the helminth competes with the host due to vitamin B ₁₂, the latter can be contained in the body of the helminth in quantities necessary to achieve therapeutic remission.

Acquired metabolic disorders of vitamin B ₁₂.

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

Symptoms of the disease appear gradually. Initially, there is a worsening of appetite, aversion to meat, dyspeptic phenomena are possible. The most pronounced anemic syndrome - pallor, light icteric skin with a lemon-yellow hue, subclicity sclera, weakness, malaise, fatigue, dizziness, tachycardia, shortness of breath even with a little physical exertion. Characteristic changes in the gastrointestinal tract - glossitis (the appearance of bright red areas of inflammation, sensitive to food intake, especially acidic), accompanied by pain and burning, it is possible the appearance of aft in the tongue. As the inflammatory phenomena subsided, the papillae of the tongue become atrophied, the tongue becomes shiny and smooth - the "lacquered tongue". From the side of the nervous system, changes are minimal, children do not have funicular myelosis. Paresthesia is most often noted - a sensation of crawling, numbness of the limbs, and others. Possible moderate hepatosplenomegaly. Sometimes, with increased hemolysis, subfebrile is noted. Possible functional changes in the gastrointestinal tract, heart. Often, patients notice a sharp decrease in gastric secretion. Due to prolonged hypoxia, the development of functional myocardial insufficiency is possible (there is a disruption of the supply of the heart muscle, its fatty infiltration).

[1], [2], [3], [4], [5], [6], [7]