Anemia it is a condition characterized by a reduced amount of hemoglobin in the circulating blood. this can happen because they are decreased erythrocytes (red blood cells) in the blood, or because they contain a low amount of hemoglobin. Anemia is therefore characterized by low hemoglobin.

L'macrocytic anemia is a type of anemia characterized by larger than normal red blood cells: blood tests will show low hemoglobin and high MCV (theMCV is the mean corpuscular volume of red blood cells, in English mean corpuscular volume). It is defined megaloblastic anemia a macrocytic anemia characterized by the presence of abnormal erythroblasts (erythroblasts are the precursor cells of the erythrocyte, ie the mature red blood cell). This type of abnormal erythroblast is called megaloblasts when it is found in the medulla and macrovalocyte when it is found in the peripheral blood (the latter term has now fallen into disuse). Megaloblastic anemia is caused by a defect in DNA synthesis resulting from a deficiency vitamin B12 (also called cyanocobalamin) and / or di folic acid (compound of the folate group).

Folic acid

L'folic acid (more precisely called pteroylglutamic acid), is a molecule consisting of three parts: pteridine, para-aminobenzoic acid from glutamic acid. Folic acid is introduced into our body with food, and is contained, in the form of polyglutamates, i.e. chains of seven or more glutamic acid residues attached to each other mainly in vegetables, in raw liver,
and in the yeast. Folic acid is mainly absorbed in a part of the intestine called proximal jejunum, thanks to the hydrolysis action of an enzyme called "conjugate", Present in the intestinal mucosa.
L'pteroylglutamic acid it is not biochemically active: it is the "progenitor" of a series of compounds called folic coenzymes, much more biochemically active, which are obtained from reduction reactions
(dihydro or tetrahydro). One of these compounds is folinic acid, or 5-formyl-tetrahydrofolic acid, a substance of fundamental importance, which, as will be seen later, is the precursor of 5-10 methylene-tetrahydrofolate, necessary in the cascade of reactions that leads to the formation DNA.

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Vitamin B12

What is vitamin B12 and what is it used for? There vitamin B12, or cyanocobalamin, it is a molecule made up of two main parts: a nucleotide (5,6-dimethyl-benzimidazole)
and a corrinic ring (planar group) with a in the center
cobalt atom.
In humans there are two main types (coenzymes) of
vitamin B12.

  1. There deoxy-adenosyl-cobalamin, present mainly in the liver, in which the anionic group linked to cobalt is 5-deoxy-adenosyl; is the coenzyme required for the conversion of methylmalonate coenzyme A into succinyl-coenzyme A. Its deficiency leads to increased excretion of methylmalonate.
  2.  There methyl-cobalamin, present in plasma, in which the anionic group is methyl; it is the coenzyme involved in the reactions with folates for DNA synthesis. Vitamin B12 also promotes the reduction of ribosides, contained in ribonucleic acid (RNA) to deoxy-ribosides, contained in DNA. It is precisely methyl-cyanocobalamin the fundamental coenzyme in the formation of red blood cells.

Where is Vitamin B12 found? Vitamin B12 is found in foods of animal origin and is resistant to cooking; It is absorbed in a section of the intestine called ileum, through a glycoprotein secreted at the level of the body and gastric fundus cells, the intrinsic factor.

After absorption, vitamin B12 is detached from the intrinsic factor, and is transported in the blood by transcobalamins, transporter proteins. Much of the cyanocobalamin is stored in our liver (at least half of the total content, which is around 2-5 mg).

Causes of megaloblastic anemia

To understand what megabloblastic anemia is and why it is characterized by larger than normal red blood cells, we will do some brief physiology of DNA and the formation of erythrocytes. DNA is an organic polymer made up of units called nucleotides (short for "deoxyribonucleotides"). All nucleotides are made up of three basic components: a phosphate group, deoxyribose (which is a pentose sugar, i.e. formed by 5 carbon atoms) and a nitrogenous base that binds to deoxyribose. There are four nitrogenous bases that can be used in the formation of nucleotides to be incorporated into the DNA molecule: adenine, guanine, cytosine is thymine while in RNA, instead of thymine, it is present uracil.
Thymine differs from uracil in that it has a extra methyl group: therefore the methylation of uracil, necessary for its conversion into thymine, is a fundamental step for the synthesis of DNA, which in turn is necessary for the cell division.

The methylation process needs a substance, 5-10 methylene-tetrahydrofolate (5-10 methylene THF), in order to be concluded effectively. Our body obtains THF from folic coenzyme N5-methyl-tetrahydrofolate, by transferring a methyl group to the vitamin B12.

In case of reduced availability of the complex offolic acid or vitamin B12, the fundamental components for this reaction are reduced, the cells of our organism will have difficulty in replicating efficiently. This applies to all cells in our body, but especially to those that have a high proliferative index, such as blood cells. in fact it is known that the red blood cells  have an average life of only 120 days, and therefore within 4 months our bone marrow will have to provide for the replacement of all the circulating red blood cells.

The deficiency of Vitamin B12 and folate, the main cause of megaloblastic anemia, is to be classified into 5 main areas:

  • Insufficient dietary intake
  • Reduced absorption (malabsorption)
  • Increased body requirement
  • Inadequate use
  • Other causes

Although the causes of Vitamin B12 deficiency and folate deficiency are often dealt with separately in books and on the web, it goes without saying that they are often actually common causes. It is clear that many times the same cause that leads to a malabsorption of vitamin B12 also leads to a poor absorption of folic acid. The same goes for the causes of low intake with nutrition.

However, it must be said that the Folic acid deficiency is a more frequent occurrence than Vitamin B12 deficiencyIn fact, folic acid stocks run out in about a month, much faster than Vitamin B12, which takes years to run out of stocks.

The main ones causes of megaloblastic anemia I'm:

Causes of insufficient dietary megaloblastic anemia

  • Incorrect nutrition: people suffering from malnutrition, vegetarians is vegans they are at risk of not getting enough vitamin B12 and folate, and thus developing pernicious anemia.

Causes of malabsorption megaloblastic anemia

  • Pernicious anemia or Biermer's disease, also called aAddison-Biermer nemia, Biermer-Ehrlich anemia, Hunter-Addison anemia, and Lebert essential anemia. It is a dtheeffect of intrinsic factor in the presence of chronic autoimmune atrophic gastritis, or chronic atrophic gastritis type A, a disease characterized by chronic inflammation of the cells of the gastric mucosa linked to the presence of autoantibodies such as intrinsic factor antibodies, anti-proton pump antibodies and gastrin receptor antibodies. 

There chronic atrophic gastritis type A represents the 10% of all cases of atrophic gronic gastritis, and is the cause of a progressive loss of the gastric glandular component, with reduced production of intrinsic factor, which is also bound by antibodies to intrinsic factor which alter its intrinsic capacity to bind vitamin B12. All this leads to a lack of absorption of vitamin B12 which can cause the appearance of megaloblastic anemia. In fact, given the particular structure of vitamin B12, its absorption is secondary to the bond with a glycoprotein called intrinsic factor, produced by the parietal cells of the fundus and body of the stomach. In the absence of intrinsic factor, only a small part of cyanocobalamin would be absorbed by simple diffusion.

  • Chronic atrophic type B gastritis: represents 90% of all cases of chronic atrophic gastritis, and is linked to chronic Helicobacter Pylori (H. Pylori), a flagellated gram negative bacterium (with small offshoots called flagella) that has a particular trophism for the gastric mucosa (ie it is at ease in the acidic environment of the stomach). For the same reason reported above, the loss of most of the gastric glands leads to a drastic decrease in the production of intrinsic factor, to a reduced absorption of vitamin B12 and to the appearance of macrocytic anemia.
  • Lack of the intrinsic factor for surgical removal of the stomach, for example following a bariatric surgery, to which severely obese people are subjected.
  • Secondary intrinsic factor deficiency a gastrectomy (surgical resection of the stomach), for example as a treatment for complicated stomach ulcers or to remove gastric carcinoma (type of cancer); the resulting reduced intrinsic factor production is a not uncommon cause of the onset of macrocytic anemia if there is not adequate supplementation of vitamin B12.
  • Secondary intrinsic factor deficiency a ileal resection, i.e. resection of the ileum, the second part of the small intestine,  which is the site of absorption of vitamin B12.
  • Intrinsic factor deficiency linked to a inherited defect in its production (it should be noted that this is a very rare condition, transmitted on a recessive genetic basis);
  • The ilectomy, that is the surgical removal of the ileum, which is the final part of the small intestine responsible for the absorption of nutrients, including vitamin B12, is a frequent cause of megaloblastic anemia.
  • Chronic inflammatory bowel diseases, such as Crohn's disease, they cause malabsorption and vitamin B12 deficiency, which can lead to the onset of macrocytic anemia.
  • Malabsorption syndromes linked to alterations of the intestinal bacterial flora, or to enteric infestation by parasites, they can lead to a lack of vitamin B12 and consequent onset of megaloblastic anemia.
  • Celiac disease in adults: changes in the intestinal villous epithelium can impair the absorption of nutrients including vitamin B12 and folic acid, resulting in the development of macrocytic anemia, characterized by low hemoglobin and high MCV.
  • Gastric hypochlorhydria or achlorhydria (reduced presence or absence of hydrochloric acid (HCl) in the stomach, it may be due, among other causes, to the intake of gastroprotective therapy with PPI (proton pump inhibitors,  such as omeprazole, lansoprazole and pantoprazole) or antacid therapy with type 2 histamine receptor antagonists (H2 antagonists such as ranitidine), very popular drugs used in combination with aspirin (acetyl salicylic acid) or for the treatment of gastroesophageal reflux and peptic ulcer.

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  • Metformin therapy, an oral hypoglycemic antidiabetic drug that can interfere with the proper absorption of vitamin B12, and cause macrocytic anemia.
  • Therapy with anticonvulsant or antiepileptic drugs
    (for example diphenylhydantoin, primidone and barbiturates), which, by inhibition of the intestinal conjugase enzyme, hinder the absorption of the polyglutamates from which folinic acid is derived.
  • Tropical sprue: disease affecting mainly in tropical and subtropical areas, characterized by megaloblastic anemia in a context of intestinal malabsorption caused by bacterial, viral or parasitic infections. The main symptoms are nausea, vomiting, watery diarrhea, weight loss (weight loss) and tiredness (asthenia).
  • Parasite infections such as enteric infestations by botriumcephalic worm, which prevents the correct absorption of vitamin B12.

Causes of increased need macrocytic anemia

In our organism there are conditions in which there is an increased cellular replication; this can happen in physiological conditions such as:

  • Pregnancy, because folic acid is necessary for the synthesis of the DNA of the embryo and fetus
  • Feeding time
  • In the premature babies

Unfortunately, there are also pathological conditions which result in increased cell proliferation:

  • Neoplasms characterized by rapid cellular growth, such as leukemia.
  • Hemolytic anemias, because there is a reduction in the life cycle of erythrocytes that undergo rapid destruction, which determines a 3-4 times increase in the erythropoietic activity of the bone marrow, with a consequent greater need for folate.
  • Inflammatory diseases (rheumatoid arthritis, Crohn's disease, exfoliative dermatitis) e metabolic diseases (thyrotoxicosis) in which there is an increased cell turnover.

Causes of megaloblastic anemia: reduced utilization

In Vitamin B12 deficiency, the folic acid present cannot be converted from folic coenzyme N5-methyl-tetrahydrofolate a 5-10 methylene-tetrahydrofolate (5-10 methylene THF). Here, even in the presence of normal amounts of folate, these are under-used by the body.

Another reason for the reduced use of folic acid is the use of some medications as the chemotherapy methotrexate, or as antibiotics (trimethoprim, co-trimoxazole or Bactrim), which they inhibit
dihydrofolic-reductase, an enzyme that converts dihydrofolate
in tetrahydrofolate.

Other causes of megaloblastic anemia

  • Antitumor therapy with drugs that interfere with DNA synthesis such as purine synthesis antagonists (6-mercaptopurine, azathioprine), pyrimidine synthesis (5-fluorouracil, 6-azauridine) or directly inhibit DNA production, such as procarbazine and hydroxyurea.
  • Lesh-Nyhan syndrome
  • Orotic-aciduria

Causes of Macrocytic Anemia

Normally it is customary to associate the term macrocytic anemia with Amegaloblastic nemia. This, while commonly accepted, is incorrect, as there are forms of macrocytic anemia that do not have circulating megaloblasts and macrovalocytes. Macrocytic anemia without megaloblastosis can be found in:

  • Some forms of hemolytic anemia, characterized by important
    hyperbilirubinemia and elevated reticulocytosis
  • Aplastic anemia with macrocytosis the appearance of red blood cells does not
    is that of macrovalocytes: characterized by a marked reduction also in white blood cells or leukocytes (leukopenia) and platelets (thrombocytopenia)
  • Leukemia
  • Sideroblastic anemia
  • Myxedema
  • Chronic alcoholism with or without cirrhosis

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  1. ivana porters 4 years ago

    Never was an explanation clearer and more useful than this !!! really thank you !!!

  2. ROCCO PENNACCHIA 4 years ago


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