Iron deficiency anemia

Iron deficiency anemia (or iron deficiency anaemia) is a common anemia that occurs when iron loss (often from intestinal bleeding or menses) occurs, and/or the dietary intake or absorption of iron is insufficient. In iron deficiency, hemoglobin, which contains iron, cannot be formed.

Iron deficiency is the most common single cause of anemia worldwide, accounting for about half of all anemia cases. It is more common in women than men. Estimates of iron deficiency world wide range very widely, but the number almost certainly exceeds one billion persons globally. Worldwide, the most important cause of iron deficiency anemia is parasitic infection caused by hookworms, whipworms, and roundworms, in which intestinal bleeding caused by the worms may lead to undetected blood loss in the stool. These are especially important problems in growing children. Malaria infections that destroy red blood cells (although the iron is recycled) and chronic blood loss caused by hookworms (where the iron is lost) contribute to anemia during pregnancy in most developing countries. In adults of post-menopausal age (over 50 years old) the most common cause of iron-deficiency anemia is chronic gastrointestinal bleeding from nonparasitic causes, such as from gastric ulcer, duodenal ulcer or a gastrointestinal cancer.

In the developed world, where intestinal worm parasite burden is less than in many undeveloped countries, about 20% of all women of childbearing age have iron deficiency anemia, compared with only 3% of adult men. The principal cause of iron deficiency anemia in these countries is blood lost during menses in premenopausal women, which is not compensated by intake from food and supplements.

Iron deficiency anemia is one result of an advanced stage iron deficiency, which is even more common. When the body has sufficient iron to meet its needs (functional iron), the remainder is stored for later use, mostly in the bone marrow, liver, and spleen (although all cells store some iron) as part of a finely tuned system of human iron metabolism. The store of iron present in all animal cells is deposited mostly in ferritin complexes. In humans each of these are in made up of 24 subunit protein molecules of two different types, with each ferritin complex carrying about 4500 iron atoms, as ferrous ions.

Iron deficiency ranges from iron depletion, which yields little physiological damage, to iron deficiency anemia, which can affect the function of numerous organ systems. Iron depletion causes the amount of stored iron to be reduced, but has no effect on the functional iron. However, a person with no stored iron has no reserves to use if the body enters a state in which it requires more iron than is being absorbed from the diet.

Symptoms and signs
Iron deficiency anemia is characterized by pallor (reduced amount of oxyhemoglobin in skin or mucous membrane), fatigue and weakness. Because it tends to develop slowly, adaptation occurs and the disease often goes unrecognized for some time. In severe cases, dyspnea (trouble breathing) can occur. Unusual obsessive food cravings, known as pica, may develop. Pagophagia or pica for ice is a very specific symptom and may disappear with correction of iron deficiency anemia. Hair loss and lightheadedness can also be associated with iron deficiency anemia.

Other symptoms and signs of iron deficiency anemia include:
 * Anxiety often resulting in OCD type compulsions and obsessions
 * Irritability or a low feeling
 * Angina
 * Constipation
 * Sleepiness
 * Tinnitus
 * Mouth ulcers
 * Palpitations
 * Hair loss
 * Fainting or feeling faint
 * Depression
 * Breathlessness on exertion.
 * Twitching muscles
 * Tingling, numbness, or burning sensations
 * Missed menstrual cycle
 * Heavy menstrual period
 * Slow social development
 * Glossitis (inflammation or infection of the tongue)
 * Angular cheilitis (inflammatory lesions at the mouth's corners)
 * Koilonychia (spoon-shaped nails) or nails that are weak or brittle
 * Poor appetite
 * Pruritus (Itchiness)
 * Dysphagia due to formation of esophageal webs (Plummer-vinson syndrome).
 * Restless Legs Syndrome

Infant development
Iron deficiency anemia for infants in their earlier stages of development may have significantly greater consequences than it does for adults. An animal made severely iron deficient during its earlier life cannot recover to normal iron levels even with iron therapy. In contrast, iron deficiency during later stages of development can be compensated with sufficient iron supplements. Iron deficiency anemia affects neurological development by decreasing learning ability, altering motor functions, and permanently reducing the number of dopamine receptors and serotonin levels. Iron deficiency during development can lead to reduced myelination of the spinal cord, as well as a change in myelin composition. Additionally, iron deficiency anemia has a negative effect on physical growth. Growth hormone secretion is related to serum transferrin levels, suggesting a positive correlation between iron-transferrin levels and an increase in height and weight. This is also linked to pica as it can be a cause.

Cause
The diagnosis of iron deficiency anemia requires further investigation as to its cause. Iron deficiency can be caused by increased iron demand or decreased iron intake, and can occur in both children and adults.

The most important cause of iron deficiency world-wide is infestation with parasitic worms (hookworms, whipworms, roundworms). Estimates of infection in the world population vary from a minimum of a billion humans to as many as 5 billion out of a total of 6 billion. In addition to parasitosis, dietary insufficiency, malabsorption, chronic blood loss, diversion of iron to fetal erythropoiesis during pregnancy, intravascular hemolysis and hemoglobinuria or other forms of chronic blood loss should all be considered, according to the patient's sex, age, and history. Other common causes include gastrointestinal blood loss due to drug therapy (often in the case of NSAIDs or aspirin), and hypochlorhydria/achlorhydria (often due to long-term proton pump inhibitor therapy). In babies and adolescents, rapid growth may outpace dietary intake of iron, and result in deficiency without disease or grossly abnormal diet.

Especially in adults over the age of 50, iron deficiency is often a sign of other disease in the gastrointestinal tract, such as chronic bleeding from any cause (for example, a colon cancer) that causes loss of blood in the stool. Such loss is often undetectable, except with special testing. In adults, 60% of patients with iron deficiency anemia have underlying gastrointestinal disorders leading to chronic blood loss, and this percentage increases with patient age. Particularly, iron deficiency in adult men from purely dietary causes is quite rare, and in such cases, other causes of iron loss must be vigorously sought until found.

Diagnosis
Anemia may be diagnosed from symptoms and signs, but when anemia is mild it may not be diagnosed from mild non-specific symptoms. Pica, an abnormal craving for dirt, ice, or other "odd" foods occurs variably in iron and zinc deficiency, but is neither sensitive or specific to the problem so is of little diagnostic help.

Anemia is often first shown by routine blood tests, which generally include a complete blood count (CBC) which is performed by an instrument which gives an output as a series of index numbers. A sufficiently low hemoglobin (HGB) by definition makes the diagnosis of anemia, and a low hematocrit (HCT) value is also characteristic of anemia. Further studies will be undertaken to determine the anemia's cause. If the anemia is due to iron deficiency, one of the first abnormal values to be noted on a CBC, as the body's iron stores begin to be depleted, will be a high red blood cell distribution width (RDW), reflecting an increased variability in the size of red blood cells (RBCs). In the course of slowly depleted iron status, an increasing RDW normally appears even before anemia appears.

A low mean corpuscular volume (abbreviated MCV) often appears next during the course of body iron depletion. It is the result of many red blood cells which are abnormally small. A low MCV, a low mean corpuscular hemoglobin (MCH) and/or Mean corpuscular hemoglobin concentration (MCHC), and the appearance of the RBCs on visual examination of a peripheral blood smear narrows the problem to a microcytic anemia (literally, a "small red blood cell" anemia). The numerical values for red blood count, blood hemoglobin, MCV, MCH, MCHC are all calculated by modern laboratory equipment.

The blood smear of a patient with iron deficiency shows many hypochromic (pale and relatively colorless) and rather small RBCs, and may also show poikilocytosis (variation in shape) and anisocytosis (variation in size). With more severe iron deficiency anemia the peripheral blood smear may show target cells, hypochromic pencil-shaped cells, and occasionally small numbers of nucleated red blood cells. Very commonly, the platelet count is slightly above the high limit of normal in iron deficiency anemia (this is mild thrombocytosis). This effect which was classically postulated to be to high erythropoietin levels in the body as a result of anemia, cross-reacting to activate thrombopoietin receptors in precursor cells which make platelets; however, this mechanistic effect has been searched for and not corroborated. Such slightly increased platelet counts present no danger, but remain valuable as an indicator even if their mechanistic origin is not yet known.

The diagnosis of iron deficiency anemia will be suggested by appropriate history (e.g., anemia in a menstruating woman or an athlete engaged in long distance running), the presence of occult blood (i.e., hidden blood) in the stool, and often by other history. For example, known celiac disease can cause malabsorption of iron. A travel history to areas in which hookworm and whipworm are endemic, may be helpful in guiding certain stool tests for parasites or their eggs.

Body store iron deficiency is diagnosed by diagnostic tests as a low serum ferritin, a low serum iron level, an elevated serum transferrin and a high total iron binding capacity (TIBC). A low serum ferritin is the most sensitive lab test for iron deficiency anemia, however serum ferritin can be elevated by any type of chronic inflammation, and so is not always a reliable test of iron status if it is within normal limits (i.e., this test is meaningful if abnormally low, but less meaningful if normal).

Serum iron levels (i.e., iron not part of the hemoglobin in red cells) may be measured directly in the blood, but these levels increase immediately with iron supplmentation (the patient must stop supplements for 24 hours), and pure blood serum iron concentration in any case is not as sensitive as a combination of total serum iron, along with a measure of the serum iron-binding protein levels (total iron binding capacity or TIBC). The ratio of serum iron to TIBC (called iron saturation or transferrin saturation index or percent) is the most specific indicator of iron deficiency, when it is sufficiently low. The iron saturation (or transferrin saturation) of < 5% almost always indicates iron deficiency, while levels from 5% to 10% make the diagnosis of iron deficiency possible, but not definitive. Saturations over 12% (taken alone) make the diagnosis unlikely. Normal saturations are usually slightly higher for women (>12%) than for men (>15%), but this may simply indicate an overall slight poorer iron status for women in the "normal" population.

Iron deficient anemia and thalassemia minor present with many of the same lab results. It is very important not to treat a patient with thalassemia with an iron supplement as this can lead to hemochromatosis (accumulation of iron in various organs especially liver). A hemoglobin electrophoresis would provide useful evidence in distinguishing these two conditions, along with iron studies.

Gold standard
Traditionally, a definitive diagnosis requires a demonstration of depleted body iron stores by performing a bone marrow aspiration, with the marrow stained for iron. Because this is invasive and painful, while a clinical trial of iron supplementation is inexpensive and non-traumatic, patients are often treated based on clinical history and serum ferritin levels without a bone marrow biopsy. Furthermore, a study published April 2009 questions the value of stainable bone marrow iron following parenteral iron therapy.

Treatment
If the cause is dietary iron deficiency, eating more iron-rich foods such as beans and lentils or taking iron supplements, usually with iron(II) sulfate, ferrous gluconate, or iron amino acid chelate ferrous bisglycinate, synthetic chelate NaFerredetate EDTA will usually correct the anemia.

Recent research suggests the replacement dose of iron, at least in the elderly with iron deficiency, may be as little as 15 mg per day of elemental iron. An experiment done in a group of 130 anemia patients showed a 98% increase in iron count when using an iron supplement with an average of 100 mg of iron. Women who develop iron deficiency anemia in mid-pregnancy can be effectively treated with low doses of iron (20–40 mg per day). The lower dose is effective and produces fewer gastrointestinal complaints. There is evidence that the body adapts to oral iron supplementation, so that iron is often effectively started at a comparatively low dose, then slowly increased.

There can be a great difference between iron intake and iron absorption, also known as bioavailability. Scientific studies indicate iron absorption problems when iron is taken in conjunction with milk, tea, coffee and other substances. There are already a number of proven solutions for this problem, including: Iron bioavailability comparisons require stringent controls, because the largest factor affecting bioavailability is the subject's existing iron levels. Informal studies on bioavailability usually do not take this factor into account, so exaggerated claims from health supplement companies based on this sort of evidence should be ignored. Scientific studies are still in progress to determine which approaches yield the best results and the lowest costs.
 * Fortification with ascorbic acid, which increases bioavailability in both presence and absence of inhibiting substances, but which is subject to deterioration from moisture or heat. Ascorbic acid fortification is usually limited to sealed dried foods, but individuals can easily take ascorbic acid with basic iron supplement for the same benefits.
 * Microencapsulation with lecithin, which binds and protects the iron particles from the action of inhibiting substances. The primary benefit over ascorbic acid is durability and shelf life, particularly for products like milk which undergo heat treatment.
 * Using an iron amino acid chelate, such as NaFeEDTA, which similarly binds and protects the iron particles. A study performed by the Hematology Unit of the University of Chile indicates that chelated iron (ferrous bis-glycine chelate) can work with ascorbic acid to achieve even higher absorption levels
 * Separating intake of iron and inhibiting substances by a couple of hours.
 * Using non-dairy milk (such as soy, rice, or almond milk) or goats' milk instead of cows' milk.
 * Gluten-free diet resolves some instances of iron-deficiency anemia, especially if the anemia is a result of celiac disease.
 * It is believed that "heme iron”, found only in animal foods such as meat, fish and poultry, is more easily absorbed than "non-heme" iron, found in plant foods and supplements.

If anemia does not respond to oral treatments, it may be necessary to administer iron parenterally (e.g., as iron dextran) using a drip or hemodialysis. Parenteral iron involves risks of fever, chills, backache, myalgia, dizziness, syncope, rash and anaphylactic shock. A follow up blood test is essential to demonstrate whether the treatment has been effective.

Iron supplementation and infection risk
Because one of the functions of elevated ferritin (an acute phase reaction protein) in acute infections is thought to be to sequester iron from bacteria, it is generally thought that iron supplementation (which circumvents this mechanism) should be avoided in patients who have active bacterial infections. Replacement of iron stores is seldom such an emergency situation that it cannot wait for such infections to be treated.

Some studies have found that iron supplementation can lead to an increase in infectious disease morbidity in areas where bacterial infections are common. For example, children receiving iron-enriched foods have demonstrated an increased rate in diarrhea overall and enteropathogen shedding. Iron deficiency protects against infection by creating an unfavorable environment for bacterial growth. Nevertheless, while iron deficiency might lessen infections by certain pathogenic diseases, it also leads to a reduction in resistance to other strains of viral or bacterial infections, such as Salmonella typhimurium or Entamoeba histolytica. Overall, it is sometimes difficult to decide whether iron supplementation will be beneficial or harmful to an individual in an environment that is prone to many infectious diseases; however this is a different question than the question of supplementation in individuals who are already ill with a bacterial infection.

Effect of vitamin and mineral supplements
There is an observed correlation between serum retinol and hemoglobin levels. Women with a low serum retinol concentration are more likely to be iron-deficient and anemic, compared to those with normal to high levels of retinol. While vitamin A deficiency has an adverse effect on hemoglobin synthesis, even a slight increase in vitamin A intake can lead to a significant rise in hemoglobin levels. However, vitamin A is less effective in alleviating severe iron-deficiency anemia. Low levels of iron in the body cannot be relieved by vitamin A supplementation alone. Additionally, a low ascorbic acid stores in the body causes an impairment in the release of stored iron in the reticuloendothelial cells. Copper is necessary for iron uptake, and a copper deficiency can result in iron deficiency. Copper deficiency can sometimes be caused by excessive zinc or vitamin C supplementation.