Dr. José Luis Fedele

Iron deficiency anemia is defined as a decrease in hematocrit and hemoglobin secondary to a decrease in the body's iron concentration.

This decrease may be due to an insufficient contribution, an increase in consumption not compensated for or an excessive loss.

The development of iron deficiency anemia occurs in several stages characterized by a gradual decrease in body iron.

Latent iron deficiency is detected first. Here there is no anemia yet and therefore it is asymptomatic, since it is a state. It is characterized by a marked decrease in iron storage, with very low ferritin and a slight or no decrease in serum iron.

Then, iron-deficiency erythropoiesis develops, where there is very low marrow iron, decreased sideremia and ferritin, and transferrin saturation less than 15%, with a still normal hemoglobin concentration.

In the end, iron deficiency anemia develops, with a decrease in the concentration of hemoglobin and hematocrit, microcytosis and hypochromia with a marked decrease in all iron parameters.

Pathophysiology

Various international studies confirm that around 30% of the world population suffers from anemia and that, in half of these cases, the etiology is iron deficiency.

For this reason, iron deficiency is the most common cause of anemia throughout the world, in all countries, not just in developing countries.

The population analysis of the so-called “risk populations” (women of childbearing age and children) shows that the prevalence is 50% in underdeveloped countries and 10% in countries with well-established prevention programs.

The human being is the living being most prone to iron deficiency.

One cause that has favored the natural propensity to iron deficiency of the human being is the change of diet over time. From essentially carnivorous (primitive hunter) to mixed with a predominance of vegetables and cereals. This change has had an impact on iron metabolism, since a heme iron (ferrous), easily absorbable from meat, was changed to non-heme iron (ferric), much more difficult to absorb.

As mentioned before, the closed metabolism of iron and the low capacity for absorption and elimination of iron tell us that most of the iron used in erythropoiesis comes from the reuse of iron stores.

In this situation, a small increase in use (children, adolescents, pregnant women), or a small but persistent loss (young women with heavy menstruation), favor the appearance of iron deficiency.

The causes of iron deficiency anemia are very diverse. (Table I).

Iron deficiency anemia due to physiological causes (increased requirements and / or repeated blood loss) are particularly frequent in growing children and women of childbearing age. In both cases, it is common that the main cause (growth, lactation, pregnancy or heavy menstruation), is added an inadequate diet, poor in meat and vitamins, for social or cultural reasons.

Physiological iron requirements, while constant throughout life, are particularly high during the second semester of intrauterine life and in adolescence. In the newborn, the iron stores received from the mother are depleted by the sixth month of life. Added to this, breast milk is often insufficient in this metal so many pediatricians choose to routinely supplement children during their first year of life.

In young women, menstruation is by far the most common cause of iron deficiency anemia, although pregnancy and breastfeeding are additional situations that can facilitate the development of iron deficiency.

Among the pathological causes, the most common cause of iron deficiency is the loss of small but repeated amounts of blood. For this reason, in an adult man or a post-menopausal woman, iron deficiency anemia forces us to always look for chronic bleeding at the digestive level.

Small-volume chronic hemorrhages are generally due to gastrointestinal tract injuries. Among the benign causes are esophageal varices (liver cirrhosis), gastritis (excess NSAIDs), gastric or duodenal ulcer, hiatus hernia, inflammatory bowel disease, diverticulosis, hemorrhoids, etc. Intestinal parasitosis (hookworm) should not be forgotten in people from certain latitudes. Malignant causes include gastric cancer, colon carcinoma, and rare small bowel tumors.

Other less common causes of blood loss through the digestive tract are vascular ectasias (telangiectasias), Rendú-Osler-Weber disease or Hereditary Hemorrhagic Telangiectasia or Idiopathic Pulmonary Hemosiderosis (Goodpasture Syndrome).

In adult women, genito-urinary blood loss can occur due to causes other than menstruation, such as uterine myomatosis, infections, gynecological or urinary tract cancers, and genito-urinary prolapses.

Exclusively urinary blood loss may be in the form of hemoglobinuria or hemosiderinuria. The latter, confirmed by the Perls stain in desquamated cells of the uroepithelium, is due to chronic intravascular hemolysis and is one of the characteristic (although not pathognomonic) symptoms of Paroxysmal Nocturnal Hemoglobinuria, as well as of certain mechanical hemolytic anemias (heart valve prostheses). mechanical).

Other less frequent losses are those caused by repeated blood donations and those caused intentionally for simulation purposes in some neurotic states.

Iron deficiency due to absorption disorders is, in our environment, much less frequent than losses. They are usually observed related to gastric resection or gastric achilia or in the course of inflammatory bowel diseases or Celiac Disease.

In relation to this last disorder, its detection as a cause of iron deficiency not explained for other reasons is increasingly frequent.

Symptoms and signs

Given that anemia is just one more manifestation of the underlying disorder that generates iron deficiency, and that in general, the onset of the anemic picture is overlapping and therefore well tolerated by the patient, many times it can go completely unnoticed by the patient until it reaches very advanced degrees of anemia. In addition, the symptoms of the same underlying disease may predominate, hiding those of anemia.

Anemia, as already mentioned, appears as a consequence of a prolonged iron deficiency erythropoiesis and the symptoms are those of any anemic syndrome.

The establishment is, in general, slow and therefore well tolerated. The hemoglobin level for the start-up of cardiovascular compensatory mechanisms ranges between 7 and 8 grams, depending on the patient's previous cardiocirculatory status.

During the state of latent iron deficiency prior to the development of anemia, some authors have described subjective symptoms such as tiredness and early muscle fatigue, but given the subjectivity of these manifestations, it is difficult to confirm these statements.

The classic symptoms such as asthenia, fatigue, hyporexia, dyspnea, palpitations, headaches, etc., appear at different stages in the evolution of the condition, also depending on the previous general condition of the patient. The marked pallor stands out, even greater than in other anemic pictures at the same hemoglobin level.

No lymphadenopathy or splenomegaly appear here except for a predisposing baseline condition.

The specific symptoms appear in those cases with a long evolution time and are due to epithelial alterations and pagophagia. Pagophagia, also known as "pica", consists of an alteration in the perception of flavors, with a compulsive need to ingest non-food products, such as ice or other substances (earth, paint, lime, etc.). Its mechanism is unknown but disappears with iron treatment.

Of the epithelial alterations, the best known is koilonychia, which consists of the progressive thinning of the nails, which become striated, brittle and a central concavity appears, which gives them the appearance of a spoon.

Other less specific but very frequent alterations are fragility and hair loss, atrophic glossitis and angular stomatitis. Sometimes the upper part of the esophagus is occluded, with an excess of cells from cell desquamation, causing dysphagia known as Plummer-Vinson or Patterson-Kelly syndrome.

Another symptom, rare to see in our times, is the blue sclera, described by Osler in 1908, which is due to their thinning with translusence of the choroid.

A certain predisposition to infections has also been described, as a consequence of lactoferrin deficiency in granulocytes, which removes their bactericidal power. Alterations in cellular immunity have also been described, due to decreases in the T lymphocyte population and in the production of lymphokines (IL-1 and IL-2) in patients with prolonged iron deficiency.

It is important to note that when faced with iron deficiency anemia, the interrogation and physical examination should guide the search, not only of the symptoms and signs of anemia per-se, but also of the potential underlying causes, which in many cases is transformed in the most important element in the evaluation of these patients.

Study methodology

The diagnosis of iron deficiency anemia requires, first, confirming the iron deficiency, and second, investigating its cause.

Confirmation of the iron deficiency character of anemia is essential, since the correct treatment will depend on it.

Today there are many tests available to confirm this deficiency.

The observation of a smear remains a cheap, simple technique that provides a lot of information.

Characteristically, iron deficiency anemias are microcytic and hypochromic.

The hypochromic character is manifested by an increase in the central pallor of the red blood cell. The measurement of erythrocyte indices, specifically MCV, which is always down, clarifies the microcytic character.

At present, the electronic measurement of the indices constitutes a fundamental criterion to consider anemia as of probable iron deficiency origin.

Measurement of the iron levels and iron deposits is another fundamental step in the diagnosis of these anemias.

The sideremia varies somewhat with age and is higher in men than in women.

In iron-deficiency anemia, it is usually below 50 ug / dl and is accompanied by a characteristic increase in the transferrin saturation capacity, which generates a low percentage of transferrin saturation. It has already been mentioned that when the saturation percentage is below 15%, it is a sign of insufficient iron supply for adequate erythropoiesis. These three elements are very useful, not only for the diagnosis of iron deficiency, but also for the differential diagnosis of other microcytic, hypochromic anemias, such as anemia of chronic diseases, which can sometimes have low sideremia values, but they never raise the saturation capacity so much and therefore the percentage never drops below 25%.

Another important element in the diagnosis of these anemias is the measurement of serum ferritin. This also undergoes variations with age and sex, but in net deficiency states it is always below 15 ng / ml (vn: 15 to 300 ng / ml).

It should not be forgotten that ferritin is an acute phase reactant protein and that it can increase in situations that have nothing to do with variations in iron stores (acute or chronic inflammatory processes). In these circumstances, the measurement of serum ferritin loses its sensitivity as a diagnostic method of iron deficiency or iron overload but acquires value as a marker of certain inflammatory processes (RA, Still's disease).

Other less widely used tests include the measurement of red cell ferritin, the determination of soluble transferrin receptors, and the measurement of red cell protoporphyrin.

Lately, the determination of soluble transferrin receptors has been given importance, which normally circulate in very low amounts in plasma, but increase greatly in iron deficiency states, and is considered, today, the most sensitive test for iron deficiency.

Erythrocyte protoporphyrin is an index of iron availability by the erythroblast. In the last step of heme formation, iron is incorporated into protoporphyrin IX. When there is a deficit of iron and it is not incorporated, protopofyrin is eliminated and thus its plasma levels rise and can be detected by sensitive techniques.

Finally, bone marrow aspirate can be used to perform Perls stain.

This test is innocuous and of great simplicity and allows to clearly differentiate deficiency states, where macrophage iron is almost absent, from chronic inflammatory states, where there is an excess of iron in medullary macrophages.

However, with the techniques available today, it is rare to have to go to the bone marrow study to diagnose iron deficiency anemia.

Once the iron deficiency character of anemia has been confirmed, the following steps should be directed towards the search for the etiological cause.

Tests such as search for occult blood in fecal matter, digestive endoscopic studies, ultrasound or abdominal tomography, gynecological and / or urological evaluation, etc., should be directed with criteria according to an adequate clinical history.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of hypochromic microcytic anemia basically comprises 3 entities:

The thalassemias are the most common cause of macrocytic hypochromic anemia after iron deficiency. Diagnosis is easily made by measuring iron levels that are low in iron deficiency and normal to high in Thalassemias. Hemoglobin electrophoresis reveals an increase in the A2 fraction in beta thalassemia and in HF in delta thalassemia. Alpha thalassemia does not produce changes in electrophoresis and DNA studies are required for its correct diagnosis. In cases where iron deficiency and thalassemia coexist, electrophoresis should be performed after a period of iron treatment.

The Anemias of Chronic Diseases , as already mentioned, are usually microcytic and hypochromic, and sometimes the levels of sideremia are usually low.

The difference is marked by the saturation capacity and the percentage of transferrin saturation, as already explained. Ferritin is usually elevated as an acute-phase reactant component, so it is of no value in these conditions. The bone marrow examination with the Perls stain characteristically shows iron-loaded macrophages with erythroblasts with very little iron, indicating a disorder in the internal transport of medullary iron.

The sideroblastic anemia is a rare disorder, which can be congenital, but most of the time is acquired, especially related to Myelodysplastic Syndromes. It presents as a microcytic, hypochromic anemia and characteristically has the presence of iron-loaded sideroblasts with a typical perinuclear or “ring” distribution, reflecting an irregular distribution of intracellular iron in the perinuclear mitochondria. This characteristic, demonstrable with the Perls stain, plus characteristic dyserythropoietic changes in the rest of the medullary elements, sealed the diagnosis of sideroblastic anemia.

Treatment of iron deficiency anemia should follow three objectives.

Treat the underlying cause, improve symptoms, and prevent recurrence.

The treatment of the etiological consists of eliminating the cause that caused the anemia.

You will be guided by timely research towards digestive or gynecological causes.

Symptomatic treatment aims to raise hemoglobin levels and restore iron stores. Oral administration of ferrous salts is preferred, but these have the disadvantage of not always being well tolerated and in these cases the parenteral route will be chosen.

There are preparations with ferrous sulfate, succinate, and gluconate salts. Ferrous salts are easily oxidizable and are usually administered in the form of capsules or tablets. Preparations usually contain approximately 30 mg of elemental iron per 100 mg of salt. In general, 200 mg tablets are available, so each tablet will provide 60 mg of elemental iron. At least 2 tablets daily are recommended (more generally does not improve absorption levels and adds undesirable effects, especially at the gastrointestinal level).

When it is decided to do treatment with parenteral iron, it can be administered intramuscularly or intravenously.

Intravenous salts are sucrose salts, generally well tolerated and with a very good response in a short time. The most serious inconvenience or side effect is the allergic reactions that can appear even in patients who have already used iron through other routes without problems, and that range from mild skin rashes such as hives, to severe anaphylactic reactions.

For this reason, it is recommended to do a “test” dose in the first infusion, with very low doses and close monitoring of the patient to anticipate a severe adverse reaction.

When intramuscular iron is used, the chance of allergic reactions is much lower. In these cases, the most common adverse event is staining of the skin at the injection site, which can take many months to resolve.

In general, iron replacement therapy should be done for several months.

It is common practice to supplement with iron until the patient corrects his anemia and then to discontinue it. In these cases, although the hemoglobin level is corrected, which is one of the goals, in general, the iron deposits are not saturated and in cases where the cause can continue to operate (eg: polymenorrhea), it is promptly you will return to a state of iron deficiency anemia.

It is for this reason that it is considered that an adequate treatment with iron supplements should never last less than three months. It is necessary to emphasize that even with an educated treatment in dose and time, a state of latent iron deficiency may persist if, as mentioned before, the cause of loss persists, and in these cases, treatment may be necessary for many months or even years .