Iron Deficiency Anemia

Iron deficiency anemia is the most common form of anemia in the world, producing red blood cells (RBCs) that are smaller than usual, and hence, the term microcytic is used when referring to them.

RBCs are not only reduced in size and number, but contain a subnormal amount of hemoglobin, which causes cells to become pale. Hypochromic is the term used when describing cells that are paler in color because they do not contain their full complement of hemoglobin.

A domino effect is produced as body stores of iron and plasma iron decrease. This also causes a reduction in transferrin, which is necessary to bind with and transport iron. Insufficient body stores of iron lead to a depleted RBC mass which, in turn, leads to a decreased hemoglobin concentration (hypochromia) and decreased oxygen-carrying capacity of the blood.

Although one may take in enough dietary iron, even iron supplements, the body cannot utilize the iron because of inefficient red blood cell production. This results in a type of a malabsorptive anemia found in such conditions as sideroblastic anemia, renal disease, vitamin deficiencies, and such red blood cell destruction disorders as hemolytic anemia, or such hemoglobinopathies as thalassemia and sickle cell anemia.

The distinction between “iron deficiency” and “anemia” is important. They often go hand in hand, but people can be iron deficient without being anemic.

Iron deficiency is a depletion of iron stores while anemia refers to the depletion of iron in the red blood cells.

These depleted red blood cells are not able to carry enough oxygen from the lungs to the tissues, causing a hindrance in energy being released from the cells and every cell in the body will feel the effect.

Another factor is that a person can have iron deficiency anemia and iron overload at the same time.

Countless unknown numbers of people worldwide are coping with these two conditions simultaneously because, while they have an excessive amount of iron in their tissues, their bodies cannot access it. The organs of these patients literally rust away because of the extraordinary accumulation of iron, while the symptoms of anemia prevail as a result of the lack of iron in the hemoglobin. Since the body is unable to excrete iron (or other metals) readily, the accumulation can soon becomes toxic. For these people, special chelating treatments are necessary.

History
There are several interesting historic tales about iron deficiency anemia. The Greek mythologic character, Iphiclus, supposedly drank iron rust dissolved in wine and was cured of impotence.

From the 16th through to the early 19th centuries, adolescent girls suffered a malady called chlorosis (“green sickness”) that caused a greenish pallor associated with palpitations, breathlessness, ankle edema, thrombophlebitis, and diffuse gastrointestinal complaints.

Around 1830, scientists defined chlorosis as a disease of the blood chracterized by anemia and lack of iron. Pierre Blaud became famous by successfully treating affected individuals with a combination of ferrous sulfate and potassium carbonate.

Between 1890 and 1920, the incidence of chlorosis decreased dramatically, not because of iron therapy, but because women stopped wearing tight-fitting corsets. Apparently, these garments compressed the liver and other abdominal organs or induced reflux of stomach contents, causing blood loss resulting from esophageal inflammation. Women who wore these corsets may have also restricted their dietary intake in the persuit of the fashionably small waist and thus contributed to several disorders.

Statistics
Globally, iron efficiency affects over two billion people. An estimated 39% of preschool children are anemic as are 52% of the pregnant women. In addition to the lack of quality foods, blood loss from parasites is the leading cause of iron-deficiency anemia in most areas of the world.

In the adult population of the US, iron deficiency anemia accounts for 30% of the population. This number soon rises when children and adolescents are factored in, since about 10% of toddlers and 10% of adolescent girls are also iron deficient. Inadequate dietary intakes of iron are seen most often in premenopausal women, infants (particularly premature or low birth-weight), children, and adolescents (especially girls).

Stages of Development
It should be noted that iron deficiency develops in stages, but blood symptoms do not develop until iron deficiency has progressed quite far to the point where brain and muscular activity may already be impaired. Unfortunately, low hemoglobin and hematocrit test results are often relied upon as the first indicators of iron deficiency.

The three overlapping stages of iron deficiency are as follows:

• Stage One: The body’s iron stores for erythropoiesis are depleted; but, at this stage, erythropoiesis remains normal as does the hemoglobin content of the maturing erythrocytes.
• Stage Two: Now, not enough iron is transported to the marrow, and iron-deficient erythropoiesis begins.
• Stage Three: This stage begins when the small, hemoglobin-deficient cells enter the circulation in increasing numbers, replacing normal erythrocytes that have grown old and have been removed from the circulation. By this time, the development of iron deficiency anemia is associated with the depleted transport of iron stores and diminished hemoglobin production.

Causes
In women, profuse menstruation (menorrhagia) and pregnancy are reasons for primary iron deficiency anemia. In males, the condition is uncommon and occurs mainly as a result of gastrointestinal bleeding, which may be the result of gastric or duodenal ulcers, hiatal hernia, esophageal varices, cirrhosis, hemorrhoids, ulcerative colitis, or carcinoma.

A daily blood loss of 2 to 4 ml is enough to cause iron deficiency anemia. Other causes in both sexes include the use of medications that cause gastrointestinal bleeding; surgical procedures that decrease stomach acidity, intestinal transit time, and absorption; insufficient dietary intake of iron; and such eating disorders as pica (the craving and eating of non-nutritional substances).

In the Western world, however, high sugar, fat, and cow’s milk intakes are often responsible for low iron levels since all of them interfere with iron absorption. The American Academy of Pediatrics (AAP) recommends that children under the age of one year should NOT drink cow’s milk because it interferes with iron absorption, causing anemia.

The AAP published the results of a University of Iowa study that found the blood content in the stool of infants fed cow’s milk was five times higher than children fed other kinds of infant formula. Researchers also concluded that the amount of lost iron was “nutritionally important”.

There are many causes for iron deficiency anemia, but the main reasons are as follows:

• an inadequate dietary intake of iron (less than 1 to 2 mg/day) as a result of a poor diet; prolonged, unsupplemented breast- or bottle-feeding of infants; or during such periods of stress as rapid growth in children and adolescents. The elderly often develop anemia as their interest in food wanes. Dieters are another group that can become anemic because they do not meet their iron need.
• Iron malabsorption prevents iron from being used and may occur because of chronic diarrhea, partial or total gastrectomy, or such other malabsorption syndromes as celiac disease (where the lining of the small intestine is damaged by the effects of gluten – the protein found in wheat and other cereal grains of the grass family)
• secondary blood loss resulting from drug-induced gastrointestinal bleeding (usually from anticoagulants, aspirin, or steroids); heavy menses; or hemorrhage from trauma, gastrointestinal ulcers, malignancy, or varices (enlarged veins, arteries, or lymphatic vessel)
• pregnancy, which diverts maternal iron to the fetus for erythropoiesis
• mechanical erythrocyte trauma caused by a prosthetic heart valve or vena cava filters

Such diseases as rheumatoid arthritis, connective tissue disorders, chronic infection, trauma or malignancy are commonly confused with mild iron deficiency anemia. Instead, they are related to anemia of chronic disease. The body will naturally withhold iron from carcinogenic or infectious entities because of their need for iron. In these cases, iron upplementation can actually contribute to the spread of disease.

Other diseases that can lead to iron deficiency include the following:

• Esophagitis is an inflammation of the esophagus and is the most common failure of the muscular valve between the esophagus and the stomach. This causes a failure to keep the highly acidic gastric contents from going back up (refluxing) into the esophagus. Since the esophageal lining is not adapted to withstand much acid, inflammation of the mucosa results and blood slowly leaks out, ultimately leading to anemia.
• Gastritis is an inflammation of the mucosa of the stomach. There are two major causes: infection from the bacterium Helicobacter pylori, and the other being various oral medications (mostly aspirin and NSAIDs [ibuprofen sold as Motrin, Advil, Midol], naproxen [Aleve], and ketoprofen [Orudis, Acton]). These drugs may be excellent for relieving pain, but their side effects are so common that some darkly refer to them as “gastroenterologist’s little helpers”.
• Peptic ulcer is a localized area of inflammation in the lining of the duodenum or stomach. The inflammation is so intense that the mucosa and underlying tissues actually break down, resulting in a crater. Not until the 1990s did researchers know the cause, which is now mainly the result of the Helicobacter bacterium.
• Benign tumors are fairly common in the lining of the gut. The most common are hyperplastic polyps which have no real medical ramification except when they become ulcerated, allowing blood to seep out and causing an iron deficiency. The common benign tumors of the colon and rectum are the adenomas, of which there are two types: tubular (also called adenomatous polyps) and the villous adenoma. Aside from chronic bleeding and a resulting iron deficiency anemia, adenomoas have the potential of turning into frank cancers.
• Cancer is the most serious cause of chronic iron loss and is the most common cancer of the gastrointestinal tract in North America. These cancers are generally slow-growing as they eat through the wall of the gut. They can also metastasize, causing daughter tumors in the lymph nodes draining the GI tract, as well as the liver. The second most important cancer of the gut is adenocarcinoma of the stomach seen more commonly in Asia and developing countries. This type has a relatively poor prognosis.

Symptoms
Because of the gradual progression of the disorder, many patients are initially without symptoms and tend not to seek medical help until the anemia becomes severe, that is, when hemoglobin levels have dropped to a certain level (about 7 or 8 g/dl). Long before the mass of the red blood cells is affected and anemia is diagnosed, a developing iron deficiency affects behavior. Even at slightly lowered iron levels, the complete oxidation of pyruvate is impaired, reducing physical work capacity and productivity, resulting in common symptoms of fatigue, weakness, and shortness of breath.

In advanced stages, decreased hemoglobin and the consequent decrease in the blood’s oxygen-carrying capacity cause the patient to develop dyspnea on exertion, fatigue, dizziness, listlessness, pale ear lobes, palms, conjunctiva, and mucous membranes, inability to concentrate, irritability, headaches, susceptibility to infection, and a tingling sensation in the fingers and toes.

Decreased oxygen perfusion causes the heart to compensate with increased cardiac output and tachycardia. Other, less common manifestations of iron deficiency include glossitis (inflammation of the tongue), angular stomatitis (fissuring at the corners of the mouth), and koilonychia (concave or “spoon” fingernails).

Although the classic symptoms of iron deficiency have long been known, another symptom is also becoming classic: a poor tolerance to cold. One way the body accelerates heat production when the environmental temperature falls involves the neurotransmitter norepinephrine and the thyroid hormones, which speed up the metabolic rate. Iron deficiency impairs temperature regulation in both animals and humans, probably by interfering with the normal production of these compounds.

Structurally or functionally altered epithelial tissue is often found in individuals with iron deficiency anemia. The nails become brittle, thin, and “spoon-shaped” or concave as a result of impaired capillary circulation. The tongue may be sore, with redness and burning, caused by atrophy of the papillae. However, these changes can be reversed within a week or two of iron replacement.

Changes may also occur in the epithelium at the corners of the mouth, causing soreness, dryness, and cracking (angular stomatitis). The tongue turns smooth, and the patient complains of dysphagia (difficulty swallowing), or may develop pica. Dysphagia is often associated with a “web” of mucous and inflammatory cells at the juncture between the hypopharynx and esophagus. These lesions may become malignant. There may also be associated neuromuscular effects, including vasomotor disturbances, numbness and tingling of extremeties, and neuralgic pain.

Since iron is a component of compounds other than hemoglobin (e.g., cytochromes, myoglobin, catalase), deficiencies are likely to alter several tissue enzymes which, in turn, may be responsible for many of the clinical manifestations.

Individuals with iron deficiency anemia also exhibit gastritis, neuromuscular changes, irritability, headache, numbness, tingling, and vasomotor disturbances. The cause of the neurologic symptoms is unclear but may be caused by hypoxia in the already compromised blood vessels. Gait disturbances are rare. Mental confusion, memory loss, and disorientation are frequently associated with anemia in the elderly and may be overlooked as “normal” changes of ageing.

Pica is a curious symptom seen in some iron-deficient individuals. They will display an unusual appetite for ice, clay, dirt, paint chips, paste, plaster, and other nonnutritious substances. Although pica is most often seen in children, in adults, pica generally manifests itself as a craving for ice and the need to chew it.

Some people have been known to eat as many as eight trays of ice a day. This behavior has been observed for years, especially in women and children of low-income groups who are deficient in either iron or zinc. There is a dramatic change within days after iron is given and long before the red blood cells respond.

Mercury poisoning can sometimes be mistaken for iron deficiency. According to Dr. Hal Huggins, a dentist who has done extensive research in the area of amalgam (mercury) fillings, chronically fatigued people are often thought to be iron deficient. However, when a CBC (complete blood count) is performed, iron levels are often found to be within normal limits. If mercury attaches to one or all of the four sulfur-binding sites on hemoglobin, the same symptoms will occur. If even one mercury atom grabs one sulfur position, the oxygen-carrying capacity of the hemoglobin drops by 25%.

On the other hand, when the CBC registers a good hemoglobin level, as well as a high hematocrit, people can still feel chronically fatigued. (Hematocrit is a term used to indicate the percentage of blood that is composed of red blood cells). This may be because the body does not recognize that it is not transporting enough oxygen, and it compensates by crowding more red blood cells into the bloodstream, producing a high concentration of low-efficiency hemoglobin. Therefore, the blood chemistry may look good, but the patient still does not feel well.

If an acutely fatigued person whose bone marrow is still functioning well and producing red blood cells, and whose hemoglobin, hematocrit, alk phos, and LDH levels are all within normal range, but yet, he/she still has very low energy levels, mercury amalgams or mercury products used should be looked at as a possible source of the chronic fatigue.

Mercury not only interferes with the red blood cell, but can also interfere with the production of a substance called coenzyme A, which is necessary for the formation of hemoglobin and cholesterol.

Red blood cells live for only 120 days and then die; but, if forced, the body is able to regenerate half of its red cells in two days. However, in doing so, there will be an elevation of two enzymes in the blood: alkaline phosphatase (alk phos) and lactic dehydrogenase (LDH). Both are measured by blood profile enzyme tests. Taking just one-quarter of the red blood cells out of commission is definitely going to be noticed by the body.

Children
Premature infants are most at risk for iron deficiency because the majority of iron transferred from the mother occurs during the last trimester. Maternal iron stores are adequate for the first five or six months in the full-term infant, but only for about two months in the premature infant(s).

Although the majority of infants with iron deficiency anemia are underweight, many are overweight because of excessive milk ingestion. These children become anemic for two reasons: milk is a poor source of iron and given almost to the exclusion of solid foods and, some infants fed cow’s milk have an increased fecal loss of blood.

Despite being chubby, these infants are pale, usually demonstrate poor muscle development, and are prone to infections. The skin color may be described as porcelain-like. It is now commonly advocated that cow’s milk should not be given to children younger than two years of age.

The exact mechanism is unknown; but iron deficiency anemia seems to enhance the leakage of plasma proteins in infants, causing edema, retarded growth, and decreased serum concentration of the proteins albumin, gamma globulin, and transferrin.

Blood loss in infants can come from a variety of causes, excluding accidents. It is not unheard of for infants to have Crohn’s disease-like symptoms beginning – usually from drinking milk – but also a reaction to cereals. Human parovirus B-19, also known as fifth disease and slapped-face disease, as well as viral hepatitis B or C are among the viruses that result in blood loss.

Bacterial infection with helicobactor (H. pylori), E. coli, S. enteritidis (salmonella) or such parasites as roundworm, hookworm, or G. lamblia are among the types of infections that can also contribute to blood loss. The heliobacter organism is one that can go unnoticed. It often runs in families and can be found in children as young as three years of age.

During the first year of life, significant hemopoietic changes occur. Fetal hemoglobin (HgF) is present for the first five months, with adult hemoglobin steadily increasing through the first half of infancy. Fetal hemoglobin causes a shortened survival of RBCs and thus a decreased number of RBCs. A common result, at two to three months of age, is physiologic anemia. High levels of HgF are thought to depress the production of erythropoietin, a hormone released by the kidney that stimulates RBC production.

Maternal iron stores are present for the first five or six months and then gradually diminish, which also accounts for lowered hemoglobin levels toward the end of the first six months. The occurrence of physiologic anemia is not affected by an adequate supply of iron. However, when erythropoiesis is stimulated, iron supplies are necessary for formation of hemoglobin.

Children deprived of iron become irritable, restless, and unable to pay attention. The precise relationship of iron deficiency anemia to behavioral and intellectual functioning is not clear; but increasing evidence suggests that iron deficiency, alone or with anemia, results in impaired cognitive skills that may or may not be reversed after corrective measures for the iron deficit.

These symptoms are among the first to appear when the body’s iron begins to fall and among the first to disappear when iron intake is increased again. Although blood tests may rule out anemia, they will not necessarily reveal an iron deficiency either. These children are often misdiagnosed with ADD/ADHD (attention deficit disorder/attention deficit hyperactivity disorder).

Since anemia develops slowly, the child learns to adapt to the declining hemoglobin level. Most children seem to have a remarkable ability to function quite well despite low levels of hemoglobin. In addition, compensatory mechanisms may delay the development of any obvious signs. Once the hemoglobin falls sufficiently, such clinical signs as muscle weakness and easy fatiguability are the first to be seen.

The skin is usually pale and may have a waxy pallor in severe anemia. Central nervous system manifestations include headache, dizziness, light-headedness, irritability, slowed thought processes, decreased attention span, apathy, and depression. Growth is retarded, along with sexual maturation in the older child. The effects on the circulatory system can be profound as it affects the heart rate and cardiac output, as well as brain activity.

Diagnosis of iron deficiency anemia is based on clinical manifestations and lab tests.