The maintenance of normal red cell mass and the synthesis of hemoglobin are normally adjusted to take care of the physiological loss of the blood elements. Anemia results when there is excessive loss or diminished replacement of red cells.
Most anemia's are deficiency diseases resulting from inadequate
tissue concentrations of iron, vitamin B12, or folic acid. Correction of the deficiency is
highly successful provided an accurate diagnosis is made. Erythropoietin is a useful
stimulator of bone marrow in certain diseases.
Iron is contained in the body in various forms, principally as hemoglobin. Normal blood contains about 15 g of hemoglobin/100 ml, and each gram of hemoglobin contains 3.4 mg of iron. It may be calculated then that the total normal blood volume contains about 2.6 g of iron.
In addition to hemoglobin, iron is contained in ferritin, the storage form for iron in the tissues, and in the serum attached to the carrier substance, the globulin transferrin. Minute quantities are also present in the cytochrome enzymes and myoglobin of muscle. Quantitatively, hemoglobin and ferritin contain the bulk of the iron in the body, amounting to a total of about 4 to 5 g.
Under normal circumstances red cells are broken down at a steady rate, their lifespan being on the order of 120 days. Most of the iron released from the breakdown of hemoglobin is reutilized. As a consequence, the daily iron requirement in a normal adult is quite low, about 1 mg. Growth, menstruation, and pregnancy increase the iron requirement.
Perhaps the most remarkable fact about the metabolism of iron is the inability of the body to get rid of significant quantities of this element. Only minute quantities are excreted into the feces, and the urinary loss of iron is even less. This is the reason for the very low iron requirement of normal persons.
Since the body does not readily eliminate iron, there must be a mechanism that limits its absorption. Otherwise the iron content of the body would steadily increase and hemochromatosis would develop. The mechanism that limits the absorption of iron from the intestine is often referred to as the mucosal block.
The mucosal cells of the duodenum and proximal jejunum take up iron but transfer only a variable portion of it to the blood. The remainder stays in the cells probably as ferritin and is eventually lost as the cells are sloughed. Iron absorption has the characteristics of a facilitated or active transport. Other metals such as cobalt and manganese may cause competitive inhibition.
The normal daily diet contains approximately 20 mg of iron. Of this, only about 10% is absorbed, but this quantity is adequate for taking care of the very small daily losses of iron. In iron-deficiency anemia, however, the dietary iron is quite insufficient for reasonably rapid correction of the hemoglobin deface, even though the mucosal block is greatly diminished.
In addition to the mucosal block, other factors influence the absorption of iron. It is generally believed that ferrous iron is more effectively absorbed than the ferric form. On the other hand, a diet rich in phytate, phosphate (milk), or alkalinizing agents such as used for patients with peptic ulcer tends to decrease absorption of iron.
Dosages of therapeutic iron preparations should be calculated on the basis of their elemental iron content. For the treatment of iron-deficiency anemia in adults a dose of 50 to 100 mg of elemental iron three times daily is recommended.
The oral iron preparations tend to produce nausea and vomiting through a local irritant effect on the stomach. For this reason the preparations are generally administered immediately after meals. Large doses of ferrous sulfate and of ferrous gluconate have produced poisoning in children. If large amount of iron are absorbed, it seems that symptoms resembling those of heavy metal poisoning may result.
Parenteral iron should not be used unless oral preparations cannot be tolerated by the patient. Serious reactions may occur, particularly in patients who are also receiving oral iron preparations. Under these circumstances, transferrin is saturated, and the administration of parenteral iron will produce elevated concentrations of unbound metal.
The effectiveness of therapy with ferrous sulfate manifests itself
in a rise of the reticulocyte count within 7 days, an increase in hemoglobin levels by 1
to 2 g/100 ml within 3 weeks, and evidence of clinical improvement in 2 to 3 weeks.
Vitamin B12 (cyanocobalamin) is a cobalt-containing compound having a molecular weight of 1400. Its isolation from liver brought to a successful conclusion more than 20 years of investigation aimed at finding the cause of pernicious anemia.
until 1926 pernicious anemia was entirely incurable. At that time the key observation was made that large amounts of liver had a beneficial effect in the treatment of the disease. Subsequent work was aimed at purification of the liver factor responsible for the curative effect. Soon injectionable purified liver extracts of great potency were available.
The problem of pernicious anemia appeared more complex, however, than a simple deficiency of a liver factor. Clinical experiments showed that normal gastric juice contained an intrinsic factor that had to interact with a dietary extrinsic factor in order for the erythrocyte maturation factor present in liver to be obtained.
When folic acid was isolated in 1943, it was believed at first that the compound was in some way related to the etiology of pernicious anemia. It was soon found, however that whereas folic acid could remedy the hematological manifestations of the disease, it either had no effect or aggravated the neurological symptoms. Since liver extract was effective against both these aspects of pernicious anemia, it was cleat that folic acid could not represent the liver factor.
The picture became clarified when vitamin B12 was isolated in 1948. It appears that the absorption of vitamin B12 requires the presence of intrinsic factor. This is lacking in true addisonian pernicious anemia. Furthermore, injected vitamin B12 remedies both hematological and neurological disturbances in pernicious anemia. When reasonable doses of the vitamin are administered by mouth to patients with pernicious anemia, they are ineffective unless some normal gastric juice is given simultaneously. Thus there is little doubt at present that vitamin B12 represents both the extrinsic factor and the erythrocyte maturation factor. The function of the intrinsic factor has to do with the absorption of vitamin B12.
The vitamin has been called cyanocobalamin and is only one member of several cobalamins, all of which have vitamin B12 activity. The compound has been isolated not only from liver bur also from fermentation liquors of Streptomyces griseus, the organism that produces streptomycin.
Unlike many other vitamins, vitamin B12 is not present in higher plants but can be synthesized by certain microorganisms. Human liver contains at least 400 g of the vitamin/kg, and beef liver may contain up to 100 g/kg. Cow's milk contains more than human milk, up to 4 g/L.
The vitamin is indicated in treatment of megaloblastic states caused by a deficient supply or absorption of vitamin B12. In the majority of cases the deficiency is in the absorption. This is certainly the case in pernicious anemia and is noted in 6-10% of patients with monoclonal gammopathy, thus it is important to evaluate B12 status in patients with monoclonal gammopathies in general and not to assume that the megaloblastic changes in the red cells are secondary to the abnormal protein.
When 0.5 g of labeled vitamin B12 was administered orally to normal persons, about 31% was excreted in the feces. In patients with pernicious anemia the fecal excretion averaged 88%. When an intrinsic factor preparation was administered simultaneously, the excretion of the vitamin in patients with pernicious anemia decreased to normal levels. Fecal excretion of the labeled vitamin was also very high in patients following gastrectomy. On the other hand, in megaloblastic anemia of pregnancy there is no deficiency in the absorption of vitamin B12.
Vitamin B12 does not appear in urine under normal circumstances, probably because the compound is bound to plasma proteins. However, if a large dose of nonlabeled vitamin B12 (1000 g) is injected intramuscularly following oral administration of the labeled compound, normal individuals excrete as much as 30% of the radioactivity in the urine within 24 hours. Apparently, the non radioactive material displaced the labeled compound from its binding sites. This observation has been adapted to the diagnosis of pernicious anemia, since under similar circumstances as patient suffering from the disease will excrete only insignificant quantities in the urine, usually less than 2.5% of the administered dose.
vitamin B12 and folic acid correct megaloblastosis by influencing DNA synthesis. The characteristic delayed nuclear maturation in megaloblastosis results from inadequate DNA synthesis, a consequence of deficiencies of vitamin B12 and/or folic acid.
Vitamin B12 deficiency is treated by managing the cause and/or
supplementing B12. In patients with pernicious anemia and monoclonal gammopathy,
injections are necessary. In megaloblastic anemia's caused by vitamin B12 deficiency, a
characteristic reticulocyte response appears within 10 days. Some signs of improvement in
the general condition of the patient may develop within 48 hours.
Folic acid is a growth factor for certain microorganisms such a streptococcus faecalis R. Its deficiency causes anemia and leucopenia in monkeys and in humans. Folic acid has been synthesized.
Folinic acid is the reduced and active form of folic acid.
The reactions in which folic acid participates are important in the synthesis of DNA. As a consequence, deficiency of folic acid, whether induced by dietary means or by administration of the folic acid antagonists such as Methotrexate, leads to damage in those tissues in which DNA synthesis and turnover are rapid (fast dividing cells). These include the hematopoietic tissues, the mucosa of the gastrointestinal tract, and the developing embryo.
Folic acid is available in capsules and tablets containing 5 mg. The vitamin is well absorbed from the gastrointestinal tract, and injectable preparations, although available, are generally unnecessary.
The main use for folic acid is in nutritional macrocytic anemia, certain cases of sprue, pregnancy, certain cases of megaloblastic anemia in infancy, and scurvy.
It is contraindicated in pernicious anemia. It should not be used in
multiple vitamin preparations because it would obscure the diagnosis of unrecognized
pernicious anemia. Although it improves the megaloblastic anemia in this instance, it does
not protect against the nervous system manifestations of the disease and may even
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