Vitamin B12 deficiency causes

Oxidation of fatty acids with an odd number of carbons proceeds two carbons at a time (pro ducing acetyl CoA) until the last three carbons (propionyl CoA). This compound is con verted to methylmalonyl CoA (a reaction requiring biotin), which is then converted to succinyl CoA by methylmalonyl CoA mutase (requiring vitamin B )- A genetic error in the mutase or vitamin B12 deficiency causes methylmalonic acidemia and aciduria. 

How does a vitamin B12 deficiency cause a decrease in the hematocrit and hemoglobin concentration ... 

A. Pernicious anemia occurs when the stomach does not produce adequate intrinsic factor for absorption of vitamin B12, which is required for the conversion of methylmalonyl CoA to succinyl CoA and homocysteine to methionine. A vitamin B12 deficiency results in the excretion of methylmalonic acid and an increased dietary requirement for methionine. The methyl group transferred from vitamin B12 to homocysteine to form methionine comes from 5 -methyl tetrahydrofolate, which accumulates in a vitamin B12 deficiency, causing a decrease in folate levels and symptoms of folate deficiency, including increased levels of FIGLU and decreased purine biosynthesis. 

Macrocytic or magaloblastic anemia is caused by disturbances of DNA synthesis. It occurs, for example, in both folic acid and vitamin B12 deficiencies. Hematopoesis is slowed down due to reduced DNA synthesis and a reduced number of abnormally large (macrocytic) and hemaglobin-rich (hyperchromic) erythrocytes is released. 

Die neurological disorder associated with severe vitamin B12 deficiency is termed funicular myelitis. Vitamin B12 deficiency leads to disturbed choline-, phospholipid-, and nucleic-acid synthesis, resulting in spinal marrow damages. Disturbed myelin synthesis finally causes irreversible neurological failure. In addition, there are psychiatric disturbances (disturbed memory, apathy). 

When funicular myelitis occurs in advanced stages of vitamin B12 deficiency, patients are given 250 pg vitamin B12/d during the first 2 weeks of treatment to alleviate the symptoms and to replenish the stores. If the deficiency has been caused by disturbed vitamin B12 absoiption, lifelong monthly injections of 100 pg vitamin B12 are indicated [2]. 

Tests to exclude possible causes of dementia include a depression screen, vitamin B12 deficiency, thyroid function tests [thyroid-stimulating hormone (TSH) and free triiodothyronine and thyroxine], complete blood cell count, and chemistry panel.21... 

The underlying cause of anemia (e.g., blood loss iron, folic acid, or vitamin B12 deficiency or chronic disease) must be determined and used to guide therapy. As discussed previously, patients should be evaluated initially based on laboratory parameters to determine the etiology of the anemia (see Fig. 63-3). Subsequently, the appropriate pharmacologic treatment should be initiated based on the cause of anemia. 

Clearly this patient has both clinical and haematological symptoms of severe anaemia. The cause is too few red cells low RBC count and PCV but the erythrocytes which are present contain a higher than usual concentration of haemoglobin (MCHC result). Iron deficiency and vitamin B12 deficiency can be ruled out by the high serum ferritin and normal MCV results respectively. The negative HbS screen rules out sickle cell anaemia which is fairly common in Africans. 

A frequent cause of vitamin B12 deficiency is atrophic gastritis leading to a lack of intrinsic factor. Besides megaloblastic anemia, damage to mucosal linings and degeneration of myelin sheaths with neurological sequelae will occur (pernicious anemia). 

Administration of FA can mask a vitamin B12 deficiency. Vitamin B12 is required for the conversion of methyltet-rahydro-FA to tetrahydro-FA, which is important for DNA synthesis (B). Inhibition of this reaction due to B12 deficiency can be compensated by increased FA intake. The anemia is readily corrected however, nerve degeneration progresses unchecked and its cause is made more difficult to diagnose by the absence of hematological changes. Indiscriminate use of FA-containing multivitamin preparations can, therefore, be harmful... 

The main causes for vitamin B12 deficiency are impaired absorption due to a lack of gastric intrinsic factor (e.g. pernicious anemia), ileal abnormalities, or it can be the result of a strictly vegetarian diet. 

A deficiency of vitamin B12 causes the accumulation of homocysteine due to reduced formation of methylcobalamin, which is required for the conversion of homocysteine to methionine (Figure 33-3, section 1). The increase in serum homocysteine can be used to help establish a diagnosis of vitamin B12 deficiency (Table 33-2). There is concern that... 

The most common causes of vitamin B12 deficiency are pernicious anemia, partial or total gastrectomy, and conditions that affect the distal ileum, such as malabsorption syndromes, inflammatory bowel disease, or small bowel resection. 

Almost all cases of vitamin B12 deficiency are caused by malabsorption of the vitamin therefore, parenteral injections of vitamin B12 are required for therapy. For patients with potentially reversible diseases, the underlying disease should be... 

Folate deficiency results in a megaloblastic anemia that is microscopically indistinguishable from the anemia caused by vitamin B12 deficiency (see above). However, folate deficiency does not cause the characteristic neurologic syndrome seen in vitamin B12 deficiency. In patients with megaloblastic anemia, folate status is assessed with assays for serum... 

Folic acid deficiency, unlike vitamin B12 deficiency, is often caused by inadequate dietary intake of folates. Patients with alcohol dependence and patients with liver disease can develop folic acid deficiency because of poor diet and diminished hepatic storage of folates. Pregnant women and patients with hemolytic anemia have increased folate requirements and may become folic acid-deficient, especially if their diets are marginal. Evidence implicates maternal folic acid deficiency in the occurrence of fetal neural tube defects, eg, spina bifida. (See Folic Acid Supplementation A Public Health Dilemma.) Patients with malabsorption syndromes also frequently develop folic acid deficiency. Patients who require renal dialysis develop folic acid deficiency because folates are removed from the plasma during the dialysis procedure. 

Vitamins and minerals, whose main dietary sources are other than fruits and vegetables, are also likely to play a significant role in the prevention and repair of DNA damage, and thus are important to the maintenance of long-term health. Vitamin B12 is found in animal products, and deficiencies of B12 cause a functional folate deficiency, accumulation of the amino acid homocysteine (a risk factor for heart disease),46 and chromosome breaks. B12 supplementation above the RDA was necessary to minimize chromosome breakage.47 Strict vegetarians are at increased risk for developing vitamin B12 deficiency. 

Vitamin B12 deficiency normally results from indequate absorption rather than inadequate dietary intake. Pernicious anaemia is caused by vitamin B12 deficiency symptoms include anaemia, glossitis, fatigue and degeneration of the peripheral nervous system and hypersensitivity of the skin. The adult RDA and RNI for B12 are 2 and 1.5 figday- respectively. Unlike other vitamins, B12 is obtained exclusively from animal food sources, such as meat, fish, poultry, eggs, shellfish, milk, cheese and eggs. Vitamin B12 in these foods is protein-bound and released by the action of HC1 and pepsin in the stomach. 

In this hereditary disease up to 1 - 2 g of methylmalonic acid per day (compared to a normal of <5 mg/day) is excreted in the urine, and a high level of the compound is present in blood. Two causes of the rare disease are known/ One is the lack of functional vitamin B12-containing coenzyme. This can be a result of a mutation in any one of several different genes involved in the synthesis and transport of the cobalamin coenzyme.6 Cultured fibroblasts from patients with this form of the disease contain a very low level of the vitamin B12 coenzyme (Chapter 16), and addition of excess vitamin B12 to the diet may restore coenzyme synthesis to normal. Among elderly patients a smaller increase in methylmalonic acid excretion is a good indicator of vitamin B12 deficiency. A second form of the disease, which does not respond to vitamin B12, arises from a defect in the methylmalonyl mutase protein. Methylmalonic aciduria is often a very severe disease, frequently resulting in death in infancy. Surprisingly, some children with the condition are healthy and develop normally.3 1... 

Vitamin B12 is available in pure form for oral administration or in combination with other vitamins and minerals for oral or parenteral administration. The choice of a preparation always must be made with recognition of the cause of the deficiency. Although oral preparations may be used to supplement deficient diets, they are of relatively little value in the treatment of patients with deficiency of intrinsic factor or ileal disease. Even though small amounts of vitamin B12 may be absorbed by simple diffusion, the oral route of administration cannot be relied upon for effective therapy in the patient with a marked deficiency of vitamin B12 and abnormal hematopoiesis or neurological deficits. Therefore, the preparation of choice for treatment of a vitamin B12-deficiency state is cyanocobal-amin, and it should be administered by intramuscular or deep subcutaneous injection. 

Pernicious anemia associated with gastric atrophy is the most common cause of clinically apparent vitamin B12 deficiency in North American and European populations. 

Anyone with the condition phenylketonuria (PKU), a metabolic disorder, should be particularly careful about nitrous oxide use. Individuals with PKU require a diet that is high in protein in low in animal fats, which frequently results in a vitamin B12 deficiency. Nitrous oxide can remove even more B12 from these individuals bloodstreams, possibly causing mental impairments, as well as severe nerve and brain damage. 

Vitamin B12 deficiency also occurs when the region of the distal ileum that absorbs the vitamin B12-intrinsic factor complex is damaged, as when the ileum is involved with inflammatory bowel disease, or when the ileum is surgically resected. In these situations, radioactively labeled vitamin B12 is not absorbed in the Schilling test, even when intrinsic factor is added. Other rare causes of vitamin B,2 deficiency include bacterial overgrowth of the small bowel, chronic pancreatitis, and thyroid disease. Rare cases of vitamin B12 deficiency in children have been found to be secondary to congenital deficiency of intrinsic factor and congenital selective vitamin Bi2 malabsorption due to defects of the receptor sites in the distal ileum. 

Examination of the bone marrow, although important, will only confirm that the hemopoiesis is megaloblastic. A deficiency of folic acid will also cause a megaloblastic anemia and it is not possible to identify the cause on the basis of morphology. A serum assay of both vitamins will usually indicate which is responsible. If the patient is vitamin B12 deficient, the next step is to carry out a vitamin B12 absorption test to confirm that the deficiency is due to a lack of intrinsic factor. Preferably this should not be done until the patient s vitamin B12 and hemoglobin levels have returned to normal, since the gastric and intestinal cells are also affected by a lack of vitamin B12 aborption may be less than optimal if it is attempted too early. Patients with pernicious anemia also have a histamine-fast achlorhydria and gastric atrophy. The disease appears to have an autoimmune basis and antibodies to intrinsic factor can be demonstrated in the serum of more than half of affected patients. 

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