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Anemia


* Please note that most treatment modalities listed below are based on conventional medicine. PreventDisease.com does not advocate the use of any pharmaceutical drug treatments. Long-term drug therapy is very detrimental to human health. All drug information is for your reference only and readers are strongly encouraged to research healthier alternatives to any drug therapies listed.


WHAT IS ANEMIA AND SOME OF ITS CAUSES?



General Description of Anemia


Anemia is an abnormal reduction in red blood cells. It is a great problem globally and worse in developing countries, but by no means absent in industrialized nations. Anemia can occur from a malfunction at any point in the production, recycling, or regulating of red blood cells. [See Box Blood.] Anemia is not a single disease but a condition, like fever, with many possible causes and many forms.

Anemia most commonly occurs as a result of the following conditions:

  • Low iron levels (iron deficiency anemia).

  • Inhibition of erythropoietin production by the immune system (anemia of chronic disease).

  • Vitamin deficiencies (megaloblastic anemia).

  • Premature destruction of red blood cells (hemolytic anemia).

  • Replacement of normal bone marrow cells by cancer cells (myelophthisic anemia).

  • Injury to bone marrow (aplastic anemia).

  • An inborn structural defect in red blood cells (eg, sickle-cell anemia).

  • An inability to manufacture hemoglobin.

  • An inability or make use of normal or even high levels of iron (sideroblastic anemia).

  • Thyroid deficiency.
It is impossible to discuss each type of anemia here, so this report focuses on three of the most common types:

  • Iron deficiency anemia.

  • Megaloblastic anemia.

  • Anemia of chronic disease (ACD).
Some less common causes and types of anemia are included in the table below.


BLOOD



Blood Components


Blood has two major components:

  • Plasma is a clear yellow liquid that contains proteins, nutrients, hormones, electrolytes, and other substances. It constitutes about 55% of blood.

  • White and red blood cells and platelets make up the balance of blood. The white cells are the infection fighters for the body, and platelets are necessary for blood clotting. The important factors in anemia, however, are red blood cells.


Red Blood Cells


Red blood cells (RBCs), also known as erythrocytes, carry oxygen throughout the body to nourish tissues and sustain life. Red blood cells are the most abundant cells in our bodies; men have about 5,200,000 and women about 4,700,000 per cubic millimeter of blood. To understand red blood cells and their role in anemia, it is useful to know certain facts about them.


Hemoglobin


Each red blood cell contains between 200 and 300 hemoglobin molecules. Hemoglobin is a complex molecule and the most important component of red blood cells. It is composed of protein and an iron-containing molecule called heme, which binds oxygen in exchange for carbon dioxide in the lungs. The oxygenated red blood cells are then transported to the body's tissues, where the hemoglobin releases the oxygen in exchange for carbon dioxide and the cycle repeats. The oxygen is used in the mitochondria, the power source within all cells.


Structure and Shape


Red blood cells are extremely small and look something like tiny, flexible inner tubes. This unique shape offers many advantages:

  • It provides a large surface area to absorb oxygen and carbon dioxide.

  • Its flexibility allows it to squeeze through capillaries, the tiny blood vessels that join the arteries and veins.


Blood Cell Production (Erythropoiesis)


The actual process of making red blood cells is called erythropoiesis. (In Greek, erythro means "red" and poiesis means "the making of things.") The process of manufacturing, recycling, and regulating the number of red blood cells is complex and involves many parts of the body:

  • The body carefully regulates its production of red blood cells so that enough are manufactured to carry oxygen but not so many that the blood becomes thick or sticky ( viscous).

  • Most of the work of erythropoiesis occurs in the bone marrow. In children younger than five years old, the marrow in all the bones of the body is enlisted for producing red blood cells. As a person ages, red blood cells are eventually produced only in the marrow of the spine, ribs, and pelvis.

  • If the body requires an increase in oxygen (at high altitudes, for instance), the kidney triggers the release of the hormone erythropoietin (EPO), a hormone that acts in the bone marrow to increase the production of red blood cells.

  • The life span of a red blood cell is between 90 and 120 days. Old red blood cells are removed from the blood by the liver and spleen.

  • There they are broken down and iron is returned to the bone marrow to make new cells.



Iron Deficiency Anemia


Iron deficiency anemia occurs when the body lacks iron to produce the hemoglobin it needs to make red blood cells. It can be caused by a number of conditions.

Iron-Poor Diets. Lack of iron in the diet is not a common cause of iron deficiency anemia. In fact, most Americans may be consuming too much iron in their diet. Most of the iron in red blood cells is recycled and reused. In general, most people need just 1 mg and menstruating women need 2 mg of extra iron each day, which a healthy diet easily provides. Iron-poor diets are only a cause of anemia in people with existing risks for iron deficiency.

Peptic Ulcers and their Causes. The bacteria H. pylori are known to be primary causes of peptic ulcers, which, in turn, is an important cause of anemia in older people. Anemia in such cases may be less likely to result from bleeding ulcers but more to impaired iron or vitamin B12 absorption caused by the presence of the bacteria. The bacteria, in fact, may also bind to iron and reduce its availability in the intestine causing iron deficiency anemia. [See also Causes of Megaloblastic Anemia, below.]

Medications (NSAIDs). Aspirin and drugs such as ibuprofen and naproxen are called nonsteroidal anti-inflammatory drugs (NSAIDs). About 70% of long-term users of these medications have some sign of gastrointestinal bleeding, although it is rarely significant enough to cause anemia.

Bleeding due to Other Medical Conditions. Iron deficiencies most commonly occur from internal blood loss due to other conditions that range in severity from hemorrhoids, heavy menstruation, or benign colon polyps to colon cancer. Very heavy periods (menorrhagia) are the most common causes of anemia in premenopausal women. Cancers of the gastrointestinal tract account for 2% of cases of iron deficiency (the rate is higher when menorrhagia is excluded).

Pica. Pica is the craving for non-food substances such as ice, starch, or clay. It is a possible cause of iron deficiency, particularly in those who eat clay or starch, which interferes with iron absorption in the stomach. To complicate matters, pica (particularly ice cravings) may also be a symptom, rather than a cause, of anemia. [See also What Are the Symptoms of Anemia? below.]

Hookworm. Hookworm infects about one billion people worldwide. It is a major cause of anemia in areas where it occurs.

Impaired Absorption of Iron. Certain intestinal diseases (e.g. inflammatory bowel disease, celiac disease) or surgical procedures that affect the gastrointestinal tract can impair the ability of the intestine to absorb iron. (Such conditions also often impair folic acid absorption as well.)

Genetic Causes. Some people are born with iron deficiency. Certain of these cases may be due to a mutation of the Nramp2 gene, which regulates a protein responsible for delivering iron to the cells.


Anemia of Chronic Disease (ACD)


Anemia of chronic disease (ACD) is generally a condition that is triggered by a persistent inflammatory process that is, in turn, a by-product of the disease-fighting immune system.

The Inflammatory Process and ACD. The process leading to anemia of chronic disease may occur in the following way:

  • The immune system activates white blood cells and releases various compounds that cause inflammation. (These blood cells may be triggered to fight the disease or they may even be part of the disease process itself.)

  • White blood cells called macrophages release small put powerful proteins known as cytokines, which are critical in the development of ACD.

  • Cytokines are indispensable for healing. However, often in chronic and inflammatory diseases cytokines are overproduced and cause serious tissue injury and in some cases, even organ damage. Specific cytokines implicated in anemia are interleukin 1 (IL-1), tumor necrosis factor (TNF), and interferons.

  • One theory on cytokines and other immune factors and their role in anemia suggests that they change the dynamics of iron circulation, causing iron to be held back from release into the developing red blood cells in the marrow. In this case, iron stores are high, but the usable iron in circulation is low. In some ACDs (such as chronic kidney failure), cytokines may blunt the effects of erythropoietin (EPO), the hormone that produces red blood cells.
Diseases Associated with ACD. The chronic diseases that are associated with this process are the following:

  • Certain Cancers. Examples include lymphomas and Hodgkin's disease.

  • Autoimmune Diseases. Examples include rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, and polymyalgia rheumatica. Diabetes type 1 deserves a separate note. Although it is an autoimmune disease and increases the risk for anemia, its effects leading to anemia in most cases are cell damage and deterioration of the stomach lining, which produce iron deficiency.

  • Long-Term Infections. Examples include urinary tract infections and osteomyelitis. Common childhood infections, such as ear infections and urinary tract infections, may also cause anemia due to inflammation. This anemia often resolves on its own but may be confused with iron deficiency.

  • Congestive Heart Disease. This heart problem has recently been added to the list of chronic diseases associated with inflammation and anemia.
These three disease groups account for about 75% of anemia associated with chronic disease, but not all cases are easily identified. It also should be noted that not all chronic diseases involve the inflammatory process and anemia. For example, high blood pressure is a chronic disease but it does not affect red blood cells.

Combination Anemias. In some cases, a combination of iron deficiencies and inflammation in ACD may be responsible for anemia in a single patient, complicating both diagnosis and treatment. For example:

  • Internal bleeding is common in some chronic diseases, particularly with those, such as rheumatoid arthritis, that are treated with NSAIDs, pain relievers that cause gastrointestinal bleeding.

  • Inflammatory bowel disease is an ACD that is also associated with iron deficiencies from both intestinal malabsorption and GI bleeding.

  • Cancer patients may have anemia caused both by internal bleeding and the disease process itself.

  • Chronic renal failure is a special case in which anemia is associated with both ACD and deficiencies in erythropoietin. Hemodialysis is used to treat this condition and also contributes to anemia.


Megaloblastic Anemia


Megaloblastic anemia is the end product of deficiencies in the B vitamins folate, vitamin B12 (also called cobalamin), or both. Such deficiencies produce abnormally large red blood cells ( megaloblastic) that have a shortened life span. Neurologic problems are also associated with these deficiencies. There are a number of conditions that can cause these deficiencies.

Causes of Vitamin B12 Deficiency. Conditions that cause vitamin B12 deficiencies include the following:

  • Pernicious anemia. Pernicious anemia is an autoimmune disease in which antibodies are tricked into attacking stomach cells. This results in impaired production of intrinsic factor (IF), a compound that is critical for absorption of vitamin B12. Pernicious anemia is diagnosed in about 1% of people over 60, with women having a higher risk than men.

  • H. pylori and atrophic gastritis. A 2000 study suggested that the H. pylori bacterium is a player in many cases of vitamin B12 deficiency. The bacteria are not only major culprits in peptic ulcers, but also are strongly associated with atrophic gastritis. This condition is a gradual loss of the stomach lining and is a known cause of vitamin B12 deficiency. (Some researchers theorize that H. pylori -induced injuries in the stomach lining may actually be the first step in the destructive process that leads to pernicious anemia.)

  • Complications of gastrointestinal surgery. Surgeries such as stomach bypass or stapling, which remove part or all of the stomach, pose a 15% to 30% chance of causing vitamin B12 deficiencies.

  • Overgrowth of intestinal bacteria.

  • Tropical sprue (an acquired malabsorption disease occurring in tropical climates).

  • Overexposure to nitrous oxide.
It should be noted that Vitamin B12 deficiency from diet is very rare, since the liver stores over a three-year supply. It usually does not occur even in alcoholism, vegetarianism, or in malnourished people with kidney failure or cancer. Since animal products are the chief source, however, true vegan vegetarians may need a supplement, fortified food, or appropriate food selection known to contain adequate amounts of this vitamin.

Causes of Folate Deficiency. The body stores only about 100 times its daily requirements for folate and can exhaust this supply within about three months if the diet is deficient in folate.

  • Poor diet coupled with alcoholism is the most common cause of folate deficiency. Alcohol abuse not only contributes to malnutrition, but alcohol causes chemical changes that can result in lower folate levels.
Any condition that disturbs the small intestine and impairs its absorption ability can cause a deficiency. Such disorders include the following:

  • Inflammatory bowel disease.

  • Celiac sprue (a sensitivity reaction to gluten).

  • Parasitic diseases such as giardiasis.

  • Short bowel syndrome.

  • Deficiencies can also be caused by high demand for folic acid caused by conditions such as cancer, pregnancy, severe psoriasis, severe hyperthyroidism, and hemolytic anemia.

  • Some drugs, including Dilantin, methotrexate, trimethoprim, and triamterene, may also hinder folate absorption.


Miscellaneous Causes of Anemia


Kidney failure and dialysis treatments are highly associated with anemia. Other disorders not related to inflammation or bleeding that cause anemia include AIDS, hypothyroidism, and leukemia. Certain conditions, including cirrhosis, congestive heart failure, and enlarged spleens, cause a back up of fluid. This produces a higher volume of blood plasma (the liquid part of blood) which can dilute red blood cells and cause anemia. Many medications increase the risk for anemia. Among them are certain antibiotics, some antiseizure medications (eg, phenytoin), immunosuppressive drugs (eg, methotrexate, azathioprine), antiarrhythmic agents (procainamide, quinidine), anticlotting drugs (aspirin, warfarin, heparin), and cancer treatments, including drugs and radiation.


Less Common Anemias


Form of Anemia

Description and Diagnosis

Causes and Risk Factors

Treatments

Aplastic Anemia

Fat cells replace bone marrow. Reduction in all types of blood cells. Formerly fatal, but now treatable. Symptoms in addition to standard anemia are bleeding in mucous membranes and skin, gingivitis, and shortness of breath.

Very rare (two to six cases per one million people). Usually found in younger patients. Cause can be a virus, self-attack of the immune system (autoimmune disease), or chemicals such as benzene and pesticides.

Transfusions, antibiotics, bone marrow transplantation, immunosuppressant drugs. (It is nearly always fatal if treated with transfusions and antibiotics alone.)

Thalassemia

Genetic blood disease caused by a defect in the rate of production of hemoglobin. The two major forms are thalassemia minor and thalassemia major (Cooley's anemia, beta thalassemia). Thalassemia minor is the more common and milder form, in which life span is normal. Thalassemia major can be serious but it is fortunately very rare.

Affects males and females equally. Most common in people of Mediterranean descent, especially Italians and Greeks. Both types of thalassemia are found in an area that extends from northern Africa and southern Europe to Thailand, including Iran, Iraq, Indonesia, and southern China. Thalassemia major is more common in families who intermarry.

No treatment necessary for thalassemia minor. Transfusions with deferoxamine (iron chelation therapy) are standard therapy. Bone marrow transplantation.

Hemolytic Anemias: Acquired

Anemia caused by hemolysis (premature destruction of red blood cells). Diagnosis considered when there is marked increase in RBC production by bone marrow.

Autoimmune hemolytic anemia is the primary type, in which antibodies produced by the immune system damage RBCs. Cause unknown or associated with disorders such as systemic lupus erythematosus or lymphoma. Other causes are toxic agents, including lead, copper, and benzene, snake and insect bites, malaria, transfusions, post-surgical complications, and drugs such as methyldopa.

Corticosteroids for autoimmune hemolytic anemia.

Hemolytic Anemias: Inherited

Hemolysis (premature destruction of RBCs) caused by sphere-shaped RBCs, which have difficulties circulating through the spleen.

Inherited defects include membrane defects, hemoglobin abnormalities, and enzyme deficiencies. Fava beans may trigger symptoms. More likely and more serious in males than females.

Blood transfusions may be necessary for some types of hemolytic anemia. Experimental trials use immune globulin. Removal of the spleen (splenectomy) may help some patients.

Sideroblastic Anemias

Group of anemias caused by impaired ability of bone marrow to produce normal RBCs. Normal to high iron levels, but iron cannot be used to make hemoglobin. In addition to the standard symptoms of anemia are jaundice, enlarged liver and spleen, fever, headache, loss of appetite, vomiting, and leg sores. Symptoms can be mild. Usually appears in childhood. Infections, trauma, and pregnancy may trigger symptoms.

Inherited or acquired after excessive alcohol use, certain medications, including chloramphenicol, or other disorders, including some cancers and rheumatoid arthritis. More common in the elderly.

Deferoxamine (Desferal) is used to remove iron. Effectiveness is increased when ascorbate is added to the regimen. Folate and pyridoxine are used, but their effectiveness is under question.

Sickle Cell Anemia

Serious, life-threatening, inherited disease. The sickle-shaped, inflexible RBC has impaired ability to squeeze through vessels. Short life span of RBC (10-20 days) causes anemia. In addition to anemia symptoms, joint and bone pain, infections, and heart failure can occur.

Disease occurs in 0.6% and the trait is found in the genetic makeup of 9% of African Americans. Also occurs in people from India and Spanish-speaking and Mediterranean regions.

Measures to avoid cycling and control pain. Including hydration, hydroxyurea, NSAIDs and Narcotic analgesics. Bone marrow transplantation. [ 58, Sickle-Cell Disease. ]






WHO BECOMES ANEMIC?



General Risk Factors for Iron Deficiency


Population Groups. Although nutritional iron-deficiency anemia has declined in industrialized nations, 500 to 600 million people (one-sixth of the world's population) are still affected by it. Even in the US, iron deficiency is the most prevalent nutritional deficiency and is highly associated with poverty.

Age and Gender. Young children and premenopausal women are at highest risk, with those in lower socioeconomic groups having double the risk of those who are middle or upper class.

Adolescent and adult men and postmenopausal women have the lowest risk. Men, in fact, are at risk for iron overload, probably because of their higher meat intake.


Risk Factors in Infants and Young Children


In general, full-term infants who are breast fed by their mothers are born with sufficient iron stores got about six months. After that, they must rely on other sources for iron. An estimated 8% of children in the US have anemia, but the percentage varies according to region. A New York study, for example, found that 10% of children under three were anemic, and a 1999 Alaskan study reported twice the prevalence in Native American children as the national average. The risk is highest in low-income homes. No child, however, is immune to iron deficiency.

Iron-deficiency anemia in infants and small children can be due to one or more of the following factors:

  • Prematurity.

  • Too early an introduction of cow's milk.

  • The use of formula that isn't iron-fortified.

  • The toddler's own preferences for iron-poor food.

  • Low consumption of foods that enhance iron absorption, such as citrus fruits. (It should be noted, however, that iron deficiency anemia in children has been associated with drinking too much fruit juice.)

  • Strict vegetarianism in small children.

  • Experts have now identified an anemia in children that is associated with inflammation from infections such as ear infections, urinary tract infections, or others.

  • One study suggested that high fat diets in children were associated with lower iron stores.


Risk Factors for Premenopausal Women


According to one report, 10% of women in their reproductive years have iron deficiencies, and between 2% and 5% have iron levels low enough to cause anemia. The risk for anemia (usually mild) in women occurs with one or more of the following conditions.

  • Heavy menstruation for longer than five days.

  • Abnormal uterine bleeding, such as from fibroids.

  • Pregnancy. About 20% of women in industrialized countries have iron deficiency during pregnancy. Multiple pregnancies and births significantly increase the risk. [ See Box Anemia and the Pregnant Woman.]


Risk Factors for Older Adults


Although a number of studies have reported that anemia is common and even underdiagnosed in older adults, middle- to upper-class older Americans are unlikely to be iron deficient. Studies suggest in fact that only about 1% of this group actually has iron deficiency anemia. (In fact, experts are concerned that many older people may be consuming too much iron, particularly from meat-rich diets. In one study, 12.9% of older middle class people had elevated iron levels, nearly all from diet.)

If iron deficiency occurs in the elderly, it is most likely to be due causes other than diet, particularly gastrointestinal bleeding or from blood loss during surgery. Elderly people without teeth whose diets depend on canned foods are vulnerable to anemia from folic acid and other vitamin deficiencies.


People with Alcoholism


People with alcoholism are at risk for anemia both from internal bleeding and vitamin B deficiencies.


People with Iron-Poor Diets


Although indications are that most Americans are consuming too much iron in their diets, some people may be at risk for dietary iron deficiencies:

  • People whose diets are high in processed foods and lack any meat.

  • Strict vegetarians. Vegetarians who avoid all animal products may have a slightly higher risk for deficiencies in iron and some B vitamins. Although dried beans and green vegetables often contain iron, it is less easily absorbed from plants than from meat. Fortunately, most commercial cereals are fortified with vitamin B12 and folic acid (the synthetic form of folate). Studies on the prevalence of anemia in vegetarians are weak. A 2001 study of British resident reported that anemia was more common in vegetarians than in meat eaters. One 1999 study found no significant differences in hemoglobin measurements between vegetarians and non-vegetarians, but a large percentage of both groups (18% of vegetarians and 13% of non-vegetarians) had low iron stores.


Chronic Illnesses


Anyone with a chronic disease that causes inflammation or bleeding is at risk for anemia.


Athletes


Working out regularly may cause some iron loss, which is comparable to that from menstruation and rarely worrisome. One 2000 study suggests that dietary choices may account for most cases of sports anemia. Intense, sustained exercise, such as that performed by marathon runners, may cause a condition called sports anemia, which may be due to slight gastrointestinal bleeding, damaged red blood cells, low iron intake, or poor intestinal absorption of iron.



ANEMIA AND THE PREGNANT WOMAN



The Effect of Pregnancy on Anemia


Iron deficiency occurs in 20% of pregnant women in developed countries. Even worse, 50% or more of women in nonindustrialized nations become iron deficient and between 30% and 50% are deficient in folic acid. Severe anemia is associated with a higher mortality rate among pregnant women. Mild to moderate anemia, however, does not pose any elevated risk.

Pregnancy increases the risk for anemia in different ways:

  • Pregnancy increases the body's demand for folic acid and therefore poses a risk for deficiencies and an increased risk for megaloblastic anemia. Low levels of folate during pregnancy increase the risk of neural tube defects in newborns.

  • Pregnancy also increases the demand for iron thus posing a risk for iron deficiency anemia. Pregnant or nursing women require 30 mg of iron per day. Maternal iron deficiency anemia is associated with increased weight or size of the placenta, a condition that may pose a risk for later high blood pressure in the offspring. Pregnant women with low hemoglobin levels (the iron-bearing component in the blood) have an elevated risk for pre-term or low birth weight infants. (It should be noted, however, that iron supplements do not appear to have any effect on these complications.)

  • Pregnancy is also associated with fluid retention, which in turn may produce high volumes of plasma (the fluid component of blood). This can dilute red blood cells, which may lead to anemia.

  • After delivery, heavy bleeding, which occurs in 5% to 10% of women who have given birth, can cause symptoms of anemia.


Diagnosing of Iron Deficiency during Pregnancy


A diagnosis of iron deficiency is problematic in pregnant women. The standard test is a measurement of ferritin levels, which are low in most people with iron deficiency. Pregnant women, however, may have high ferritin blood levels into their third trimester but still be iron deficient. A newer test that measures a factor called serum transferrin receptor may prove to be a useful way of diagnosing iron deficiency in women.


Preventing Anemia in Pregnant Women


Iron Supplements. For the past 40 years, iron supplements have been recommended for all pregnant women. This practice has been challenged recently, however. There is no clear-cut evidence that the mild iron deficiency in most pregnant women experience is harmful. In addition, iron supplement may not be completely harmless.

Some experts suggest iron supplements for the following women:

  • All pregnant women whose hemoglobin levels are less than 11 g/dl, and

  • For those whose serum ferritin levels are low in their 20th to 24th weeks of pregnancy.
On the other hand, one 1999 study conducted in Singapore suggested that women who did not take iron supplements faced an 11-fold higher risk for anemia compared to those who took supplements, but it is unknown if this risk would apply to women in other populations. More research is needed.

Folic Acid Supplements. Women who are trying to conceive, who are pregnant, and who are breast-feeding should take 400 mcg of folic acid a day. (They should be sure this is folic acid and not folate, which is the natural form but supplements at the same dose are half as potent.)


Treating Anemia during Pregnancy


Pregnant women who become anemic and require treatment may be given oral iron supplements or transfusions in severe cases. Alternatives under investigation are intravenous iron sucrose (a newer and safer form of IV iron) and erythropoietin (a hormone that stimulates red blood cell production.)




HOW SERIOUS IS ANEMIA?



Effect on Exercise Capacity


Most cases of anemia are mild, including those that occur as a result of chronic disease. Nevertheless, even mild anemia can reduce oxygen transport in the blood, causing fatigue and a diminished physical capacity. Moderate to severe iron-deficiency anemia is known to reduce endurance. (Some studies indicate that even iron deficiency without anemia can produce a subtle but still lower capacity for exercise.)


Complications of Severe or Prolonged Anemia


Because a reduction in red blood cells decreases the ability to absorb oxygen from the lungs, overtime serious problems can occur in prolonged and severe anemia that is not treated. Anemia can lead to secondary organ dysfunction or damage, including heart arrhythmia and congestive heart failure.

Certain inherited forms of anemia, including thalassemia major, pernicious anemia, and sickle-cell anemia can be life threatening. Thalassemia major and sickle-cell anemia affect children and are particularly devastating.


Effects of Anemia in Pregnant Women


Pregnant women who are anemic have an increased risk for poor pregnancy outcomes, particularly if they are anemic in the first trimester. [ See Box Anemia and the Pregnant Woman.]


Complications from Anemia in Children and Adolescents


In children, severe anemia can impair growth and motor and mental development. Proof is lacking, but one small well-conducted trial suggested that iron therapy in anemic children under two may help reverse some of these problems. (Iron deficiency in vegetarian children without anemia may cause mental impairment, but it appears to be temporary.) A long-term 2000 study reported that 11- to 15-year old children who had been severely iron-deficient during their infant years scored lower than normal children in all subjects, but particularly in written expression. They also tended to have more behavioral, general health, and emotional problems. Another study reported that teenage girls with iron deficiency, even without anemia, may have temporary memory and concentration loss.


Effects of Anemia in the Elderly


Anemia is common in older people and can have significantly more severe complications than anemia in younger adults. The following are examples of its effects from different studies:

  • A 1999 study reported higher mortality rates in anemic individuals 85 and older compared to their nonanemic peers. (The rates were higher in anemic men than in women.)

  • One study found that anemia was a strong predictor of future serious problems that were not present at the time anemia was first detected. For example, 13% of elderly people with anemia developed cancer over a ten-year period compared to 5% of nonanemic individuals. Rates of infection and peptic ulcer rates were also higher in anemic patients.

  • Elderly patients who are anemic for more than two days before heart surgery have a greater risk for complications and death.

  • According to a 2001 study, elderly patients who have hematocrit levels below 30% have lower survival rates after a heart attacks than those without anemia. (It should be noted that in the same study, half of the subjects were anemic when they had a heart attack.)

  • A strong association was noted between an increased incidence of falls and the presence of anemia.

  • One 1999 study also found an association between anemia and vascular dementia. (This form of dementia is caused by lack of oxygen to the brain. It is not related to Alzheimer's disease.)

  • Effects of Vitamin B12 Deficiencies and Pernicious Anemia.
In addition to anemia, vitamin B12 deficiency can cause neurologic damage, which can be irreversible if it continues for long periods without treatment. People with pernicious anemia, which results in an inability to absorb the vitamin, are not only at risk for neurologic damage, but also have a higher risk for stomach cancer and possibly cancer of the throat and mouth.


Anemia in Cancer Patients


Anemia is particularly serious in cancer patients. In people with many common cancers, the presence of anemia is associated with a shorter survival times. Anemia may exacerbate the toxicity of chemotherapy in elderly cancer patients.


EFFECTS OF EXCESS IRON


High iron stores can be dangerous and may be overlooked as a problem, particularly in industrialized nations. High amounts of iron have been associated with an increased risk for cirrhosis, cardiomyopathy (a disease of the heart muscles), diabetes, and certain cancers. Although a 2000 study found no higher risk for heart disease in Caucasian males with high iron stores, more research is needed to see if these results can be confirmed, especially in women and other population groups.


Excess Dietary Iron


High-meat intake in Western countries has been associated with excess iron stores. In fact, one study found that 91% of the older American population had an iron intake that was higher than recommended.


Hemochromatosis


An inherited disease called hemochromatosis is a condition in which the intestinal tract absorbs too much iron from food, which, over time can damage organs and joints. About 10% of Caucasians carry the gene. Progression is very slow, however, and the disease is treatable if diagnosed before it has caused internal injury.




WHAT ARE THE SYMPTOMS OF ANEMIA?



Common Symptoms


Symptoms of anemia vary depending on the severity of the condition. Anemia may occur without symptoms and be detected only during a medical examination that includes a blood test. When they occur, symptoms may include the following:

  • Weakness and fatigue are the most common symptoms of even mild anemia. (Even iron deficiency without anemia can reduce working capacity in some people.)

  • Shortness of breath on exertion.

  • Rapid heartbeat.

  • Lightheadedness or dizziness.

  • Headache.

  • Ringing in the ears (tinnitus).

  • Irritability and other mood disturbances.

  • Pale skin (it should be noted, however, that healthy-looking skin color does not rule out anemia if a patient has risk factors and other symptoms of anemia) .

  • Restless leg syndrome and other sleep disturbances.

  • Mental confusion.

  • Loss of sexual drive.


Unusual Symptoms


Pica. One odd symptom, and in some cases a cause of iron deficiency is pica. This is the habit of eating unusual substances, such as ice (called pagophagia), clay, cardboard, foods that crunch, or raw starch. For example, in one study, half of people whose pica took the form of pagophagia (eating at least one tray of ice every day for two months) or eating foods that crunch (such as raw potatoes, carrots, or celery) were iron deficient. The pica often stops, particularly in children, when iron supplements are given. Pica is difficult to detect because patients are often ashamed to admit to such cravings.

Frequent Breath Holding. Studies have also indicated that children who hold their breath frequently, even to the point of fainting, when angry or upset may be iron-deficient. In one study, taking iron supplements reduced this phenomenon in 88% of treated children.


Symptoms of Megaloblastic Anemia and its Causes


Symptoms of Megaloblastic Anemia. The symptoms of megaloblastic anemia from vitamin B12 or folic acid deficiencies not only include standard anemic symptoms and also the following:

  • Inflammation of the mouth ( stomatitis).

  • Inflammation of the tongue ( glossitis), which involves shrinkage at the surface and edges of the tongue.
Symptoms of Pernicious Anemia. Early neurologic symptoms of pernicious anemia are due to B12 deficiency. They include numbness and tingling, depression, memory loss, and irritability. Advanced nerve damage can cause loss of balance and staggering, confusion, dementia, spasticity, loss of bladder control, and erectile dysfunction. Folic acid deficiency does not cause neurologic damage, although people with this deficiency can be irritable, forgetful, and experience personality changes. Of concern for patients with pernicious anemia and B12 deficiency anemia is that folic acid supplements can mask the presence of this disease in its early stages but not cure it. (Only vitamin B12 is a cure.)


HOW IS ANEMIA DIAGNOSED?



Medical History and Physical Examination


The first step in any diagnosis is a physical examination to determine if the patient has symptoms of anemia and any complications. [ See What are the Symptoms of Anemia?] Because anemia may be the first symptom of a serious illness, determining its cause is very important. This may be difficult, particularly in the elderly, malnourished, or people with chronic diseases, whose anemia may be caused by one or more of a number of factors. A detailed medical, personal, and dietary history should report the following:

  • Any family or personal history of anemia.

  • A history of gallbladder disease, jaundice, or enlarged spleen.

  • Heavy menstrual bleeding in women.

  • Any occurrence of blood in the stool or other signs of internal bleeding. (Even if the patient has not observed any bleeding, nonvisible blood may present so a rectal exam and stool test are essential.)

  • Any dietary history, particularly in people who are elderly, poor, or both.
The physician should examine the patient carefully, especially checking for swollen lymph nodes, an enlarged spleen, and pale skin and nail color.


Blood Tests to Determine the Presence of any Anemia


For anemia from any cause, specific blood tests are given to determine anemia from any cause.

Blood and Hemoglobin Counts. A complete blood count (CBC) test is always performed to determine the presence of anemia. The red blood cells, or erythrocytes, and their iron-bearing component, hemoglobin, are measured.

For example, severe anemia in adults is defined by the World Health Organization as follows:

  • Hemoglobin concentrations below 7.5 mmol/L (120 g/L) in women.

  • Below 8.1 mmol/L (130 g/L) in men.
A low red blood cell (RBC) count could indicate a number of problems including bleeding or a failure by bone marrow to manufacture red blood cells.

Hematocrit. Calculating the percentage of red blood cells in blood plasma (a measurement called the hematocrit) is also important. Plasma is the liquid portion of blood. People with a high volume of plasma may be anemic even if their blood count is normal because the blood cells have become diluted.

Normal percentages are highest in the very youngest individuals and decline as people age. They also vary by gender. The following are some examples of normal range:

  • Newborns: 42% to 60%

  • Children: 35% to 45%

  • Adult males: 41% to 53%

  • Adult women: 36% to 46%
Smokers, people at high altitudes, and those who are dehydrated tend to have higher than normal hematocrit levels. Those at greater risk for low hematocrit levels include pregnant women and patients with cirrhosis, congestive heart failure, and in patients with splenomegaly.

Reticulocyte Count. Reticulocytes are immature red blood cells, and their count reflects the rate of red blood cell production. The upper normal limit is about 100.000/mL. A low count, when bleeding isn't the cause, suggests problems in production in the bone marrow. An abnormally high count indicates that the red blood cells are being destroyed in high numbers and indicates hemolytic anemia.

Blood Morphology. A blood smear viewed under a microscope allows an expert to classify the blood by its color, size, and shape (its morphology). Generally red blood cells are categorized in the following ways:

  • Pale-colored ( hypochromic) and abnormally small ( microcytic).

  • Normal colored and normal sized ( normochromic, normocytic).

  • Abnormally large ( macrocytic).
The shape of the red blood cells, which can be distorted in many blood disorders, is also important in determining a diagnosis.


Diagnosing Iron Deficiency Anemia and its Causes


There are two steps in making diagnosis in patients with symptoms of iron deficiency anemia:

  • The first step is to determine if a person is actually deficient in iron.

  • If iron stores are low, then the second step is to diagnose the cause of the iron deficiencies, which will help determine treatment.
Determining if Iron Stores are Low: The following findings are important in determining that a person is iron deficient:

  • Blood cells viewed under the microscope are pale-colored and abnormally small ( microcytic). They are also mostly uneven in shape. (These findings suggest iron deficiency but can also appear in anemia of chronic disease and thalassemia, however.)

  • Hemoglobin and iron levels are low. (These findings further suggest iron deficiency but can also occur in anemia of chronic disease.)

  • Ferritin levels are low. Ferritin is a protein that binds to iron and low levels always mean reduced iron stores. High levels in the blood, however, do not always mean that iron stores are sufficient. For example, pregnant women may have high ferritin blood levels into their third trimester but still be iron deficient. (Ferritin levels may also be normal in patients with inflammation from ACD, even if they also have low iron stores. [ See below. ])

  • In children, reticulocyte hemoglobin levels are low. (Reticulocytes are immature red blood cells and this test may be the most effective approach for diagnosing iron deficiency in children.)
Determining Causes of Iron Deficiency. When iron deficiency anemia is diagnosed, the next step is to determine what causes the iron deficiency itself.

  • Dietary iron deficiency is most common in children and infants. It rarely is an issue in adult anemia.

  • Heavy menstrual or abnormal uterine bleeding is usually the cause of iron deficiencies in young women. Increased need for iron stores during pregnancy is also a common cause in this population.

  • If internal bleeding is suspected as the cause, the gastrointestinal tract is usually the first choice as the source. A diagnosis in such cases can be often be made if the patient has noticed blood in the stools, which can be black and tarry as well as red-streaked. Often, however, bleeding may be present but not visible. In such cases, stool tests for this hidden ( occult) blood are required. Additional tests may then be needed to diagnose the precipitating condition. Endoscopy, a fiber optic tube used to view into the gastrointestinal tract, may be used in some patients, particularly the elderly when the source of bleeding is unclear. Although endoscopy is not always performed in iron deficient patients if there are no signs of GI bleeding, one study suggested that this procedure could reveal other causes, including some cancers, in many patients.
If the patient's diet suggests low iron intake and other causes cannot be established using inexpensive or noninvasive techniques, then the patient may simply be given a monthly trial of iron supplements. If the patient fails to respond, further evaluation is needed.


Diagnosing Anemia of Chronic Disease (ACD)


Usually anemia of chronic disease is recognized during the management of the primary disease and, if the anemia is mild, additional diagnostic tests are rarely needed. The following are typical findings in ACD:

  • The blood cells are normal looking.

  • Blood tests may typically show low levels of iron in the blood, but ferritin levels are normal or even high. (Low levels of ferritin, a protein that binds to iron, indicate iron deficiency.)
Differentiating between ACD and Iron Deficiency. If a patient has symptoms and test results suggestive of both anemia of chronic disease and iron deficiency anemia, bone marrow examination may be performed, although it is expensive and can be painful.

Simpler tests are being investigated as alternatives for differentiating iron deficiency form ACD. A very promising test measures a factor called serum transferrin receptor (TfR). Levels of TfR are high in iron deficiency anemia, even in patients with ACD, but they are normal or only slightly raised in ACD alone. Another test measures levels of unsaturated iron-binding capacity (UIBC) .


Diagnosing Vitamin B-Related Anemias


Physicians need a multi-step diagnostic procedure for determining vitamin B deficiencies and the anemias that cause or are caused by them. Physicians may arrive at a diagnosis of vitamin B12 or folic acid deficiencies from different routes:

  • They may diagnose deficiencies after detecting megaloblastic anemia from abnormal blood tests.

  • They may suspect vitamin deficiencies first from symptoms and history and then look for anemia.
Diagnosing Megaloblastic Anemia. Very large oval red blood cells indicate megaloblastic anemia. Abnormally shaped neutrophils (certain white blood cells) may also be present. Bone marrow aspiration may need to be performed if the disease is strongly suspected but the diagnosis is not clear.

Determining Vitamin Deficiency. Once megaloblastic anemia has been diagnosed, the physician will need to determine which vitamin deficiency is causing it. This is extremely important because if a vitamin B12-deficient patient receives folate replacement only, then irreversible nerve injuries may develop. (Even if blood tests for megaloblastic anemia are normal, patients with neurologic and psychiatric abnormalities that have no detectable cause should still be tested for vitamin B12 deficiency.)

Deficiencies may be suggested by the presence of other disorders:

  • Malnutrition, alcohol abuse, pregnancy, a history of sprue, severe psoriasis, or the use of antiseizure drugs may indicate a folic acid deficiency.

  • A history of stomach surgery, eating raw fish (which raises the possibility of tapeworm), inflammatory bowel disease, or hypothyroidism suggests vitamin B12 deficiency.
Often, vitamin B deficiencies cannot be determined by a history or symptoms alone. Blood tests are the primary indicators of both vitamin B12 and folic acid deficiencies, but even blood tests for these vitamins are not always straightforward:

  • Folic acid and vitamin B12 levels must always be measured at the same time because each vitamin may affect the other.

  • Folate levels may be temporarily low in some people who are not truly deficient.

  • Folate levels may temporarily rise in deficient people if they have just eaten foods containing the vitamin.

  • Antibiotics can interfere with B12 levels.
Measuring methylmalonic acid and homocysteine, substances in the blood that increase when levels of one or both vitamins are low, improves accuracy.

Tests for Pernicious Anemia. Once a vitamin B12 deficiency has been established and the physician has not found any intestinal abnormalities or other factors to account for the deficiency, the doctor presumes a diagnosis of pernicious anemia.

Until recently, the only methods for diagnosing pernicious anemia were either a trial of vitamin B12 injections or a urine test known as the Schilling test, which is not completely reliable. Some clinicians no longer use it because of improvement in blood tests. Other tests are used to detect antibodies to intrinsic factor and stomach cells damaged by pernicious anemia.

Pernicious anemia is simple to treat (with vitamin replacement) but it is easily missed, particularly in patients whose diets are rich in folic acid. Folic acid can mask the early symptoms of pernicious anemia but not cure it. Consequently the disease may persist until serious neurologic symptoms occur. With folic acid now a required additive in many commercial foods, some experts are concerned about an increased incidence in pernicious anemia.


HOW IS ANEMIA PREVENTED?



Dietary Recommendations for Preventing Anemia


Foods for Maintaining Healthy Iron Stores. The following are some suggestions for increasing iron levels in the diet:

  • The best foods for increasing or maintaining healthy iron levels contain absorbable iron, called heme iron . Such foods include (in order of iron-richness) clams, oysters, organ meats, beef, pork, poultry, and fish.

  • About 60% of iron in meat is poorly absorbed; this is a form called non-heme iron . Eggs, dairy products, and vegetables that contain iron only have the non-heme form. Such plants include dried beans and peas, iron-fortified cereals, bread, and pasta products, dark green leafy vegetables (chard, spinach, mustard greens, kale), dried fruits, nuts, and seeds. (One study reported that even though non-heme iron is normally less easily absorbed, people who were iron deficient absorbed 10 times the amount of non-heme iron as people with normal iron levels.)

  • Increasing intake of vitamin-C rich foods can enhance absorption of non-heme iron during a single meal, although regular intake of vitamin C does not appear to have any significant effect on iron stores. In any case, vitamin-C rich foods are healthful and include broccoli, cabbage, citrus fruits, melon, tomatoes, and strawberries. One orange or six ounces of orange juice can double the amount of iron your body absorbs from plant foods.

  • Foods containing riboflavin (vitamin B2) may help enhance the response of hemoglobin to iron. Sources include liver, dried fortified cereals, and yogurt.

  • Cooking in cast iron pans and skillets is well known to increase iron content of food. According to one study, however, boiling, steaming, or stir-frying many vegetables in utensils composed of any material significantly increases the release of iron stored in plants so it is available to the body.

  • Certain nutrients, such as tannin (found in tea) or phytic acid (found in foods such as seeds and bran) impedes the body's absorption of dietary iron. (It is commonly believed that fiber impedes iron absorption, but researchers report that it most likely has no effect.)
Sources of Vitamins B12 and Folate. Vitamins B12 and folate are important for prevention of megaloblastic anemia and good health in general.

  • The only natural dietary sources of B12 are animal products, such as meats, dairy products, eggs, and fish (clams and oily fish are very high in B12); like other B vitamins, however, B12 is added to commercial dried cereals. The RDA is 2.4 mcg a day. Deficiencies are rare in young people, although the elderly may have trouble absorbing natural vitamin B12 and require synthetic forms from supplements and fortified foods.

  • Folate is best found in avocado, bananas, orange juice, cold cereal, asparagus, fruits, green, leafy vegetables, dried beans and peas, and yeast. The synthetic form, folic acid, is now added to commercial grain products. Vitamins are usually made from folic acid, which is about twice as potent as folate. Many experts now recommend that adults have 400 mcg of folic acid daily, which is considerably higher than standard recommendations of 400 mcg of folate, which does not take into consideration the possible benefits of folate on the heart. Women who are trying to conceive, who are pregnant, and who are breast feeding should take 400 mcg of folic acid. [ See Box Anemia and the Pregnant Woman.]



Recommended Daily Allowance for Iron


The Recommended Daily Allowance of iron for people who are not iron deficient varies by age group and other risk factors. (Iron supplements are rarely recommended in people without evidence of iron deficiency or anemia.)

Children between the ages of one and three: 10 mg per day

Teenage boys: 12 mg

Premenopausal girls and women: 15 mg per day

Pregnant or nursing women: 30 mg per day

Adult men (up to age 50): 10 mg per day

Older men and women (over age 50): 10 mg




Preventing Anemia in Infants and Small Children


The main source of iron for an infant from birth to one year of age is in milk, either from breast milk, iron-fortified infant formula, or cereal. The best methods for preventing iron deficiency during infancy are the following:

  • Prolonged breast feeding. Breast fed babies have enough iron to last four to six months assuming that the mother had adequate iron stores during pregnancy. Some infants who are only breast fed for the first year do not become iron-deficient although it is not determined what factors in the mother, child, or both are responsible for this protection. Breast milk itself is low in iron, but if the mother's diet is healthy, vitamin C and lactose in the breast milk may enhance iron absorption.

  • Avoiding cow's milk and unfortified formulas. If infants are given formula, the American Academy of Pediatrics strongly discourages the use of low-iron formulas (less than 4.0 mg/L). A 2000 study found no adverse effects in even older infants and toddlers who had been given a high-iron containing formula.

  • Introducing iron-fortified foods or supplements. Foods supplemented with iron and vitamin C are usually introduced at around six months of age in full-term infants. Premature infants should receive iron supplements no later than two months after birth. Supplements should continue for the first year of life in these children. Some experts even recommend that all children between ages one and two be given daily iron drops or iron-fortified vitamins or drinks, although this is controversial.


WHAT ARE THE TREATMENTS FOR ANEMIA?



General Guidelines


Treatment of Iron Deficiency. Iron supplements are the most effective agents for restoring iron levels in anyone who is deficient, but they should be used only when dietary measures have failed. It should be noted that they will not correct anemias that are not due to iron deficiency. One study reported that physicians prescribed iron pills for 64% of patients with anemia without performing tests to confirm whether iron deficiency was actually the cause. The study suggested that iron replacement was appropriate in less than half of these patients. Iron replacement therapy can cause gastrointestinal problems, sometimes severe ones. Excess iron may also contribute to heart disease, diabetes, and certain cancers. No one should take iron supplements if they have a healthy diet and no indications of iron deficiency anemia.

Treatment of Anemia of Chronic Disease. In general, the best treatment for anemia of chronic diseases is treating the disease itself. In some cases, iron deficiency accompanies the condition and requires iron replacement. Erythropoietin, most often administered with intravenous iron, is being investigated with success in some patients.

Treatment of Megaloblastic Anemia. The standard treatments for megaloblastic anemia are vitamin B12 injections and folic acid replacement.


Iron Supplements


Supplement Forms. To replace iron, the preferred forms of iron tablets are ferrous salts, usually ferrous sulfate (Feosol, Fer-In-Sol, Mol-Iron). Other forms include ferrous fumarate (Femiron, FerroSequels, Feostat, Fumerin, Hemocyte, Ircon), ferrous gluconate (Fergon, Ferralet, Simron), polysaccharide-iron complex (Niferex, Nu-Iron), and carbonyl iron (Elemental Iron, Feosol Caplet, Ferra-Cap). Specific brands and forms may have certain advantages. The following are some examples:

  • Prolonged-release ferrous sulfate (Slow Fe) may enhance iron absorption with fewer side effects than standard ferrous sulfate pills.

  • FerroSequels contains a stool softener, which helps prevent constipation.

  • Polysaccharide-iron complex has fewer side effects and equal absorption rates compared to ferrous salts. It is very expensive, however.

  • Carbonyl iron is composed of very fine tiny uniform spheres of iron powder and may prove to be less toxic than ferrous iron.

  • Coated or combination pills do not appear to offer any additional advantages and may hinder absorption of the iron.

  • Regimen. The general guidelines for iron replacement are as follows:

  • For adults, physicians usually advise one ferrous sulfate tablet (300 mg) three times a day.

  • Iron replacement doses for children with deficiencies are significantly lower. In general. They are given as drops or syrup administered three times a day. A single-dose daily regimen is showing promise. IMPORTANT: As few as three adult iron tablets can poison children, even fatally. This includes any form of iron pill.
No one, even adults, should take a double dose of iron if one is missed.

Other tips for taking iron are as follows:

  • For best absorption, iron should be taken between meals. (Iron may cause stomach and intestinal disturbances, however, and some experts believe that low doses of ferrous sulfate can be taken with food and absorbed without side effects.)

  • One should always drink a full eight ounces of fluid with an iron pill.

  • Tablets should be kept in a cool place. (Bathroom medicine cabinets may be too warm and humid, which may cause the pills to disintegrate.)

  • One study suggested that iron supplements impeded the absorption of non-heme iron (found in legumes and other vegetables) but not heme iron (contained in meat).
Full recovery takes six to eight weeks. (Recovery will take longer in people with internal bleeding that is not under control.) Iron replacement therapy must continue for about six months, even if anemia has been reversed. Treatment must be continued indefinitely for people with chronic bleeding; in such cases, iron levels should be closely monitored.

Side Effects. Common side effects of iron supplements include the following:

  • Constipation and diarrhea are very common. They are rarely severe, although iron tablets can aggravate existing gastrointestinal problems such as ulcers and ulcerative colitis.

  • Nausea and vomiting may occur with high doses, but can be controlled by taking smaller amounts. Switching to ferrous gluconate may help some people with severe gastrointestinal problems.

  • Black stools are normal when taking iron tablets. In fact, if they do not turn black, the tablets may not be working effectively. This tends to be a more common problem with coated or long-acting iron tablets.

  • If the stools are tarry looking as well as black, if they have red streaks, or if cramps, sharp pains, or soreness in the stomach occur, gastrointestinal bleeding may be causing the iron deficiency and the patient should call the physician promptly.

  • Acute iron poisoning is rare in adults but can be fatal in children who take adult-strength tablets.
Interactions with Other Drugs. Certain medications, including antacids, can reduce iron absorption. Iron tablets may also reduce the effectiveness of other drugs, including the antibiotics tetracycline, penicillamine, and ciprofloxacin and the anti-Parkinson's Disease drugs methyldopa, levodopa, and carbidopa. At least two hours should elapse between doses of these drugs and iron supplements.

Supplementary Agents. The following agents may improve iron absorption:

  • Adding either ascorbic acid (vitamin C) or succinic acid to ferrous sulfate therapy will improve absorption of iron stores. Ascorbic acid added to iron therapy, however, may exacerbate some of the side effects. Succinic acid added to ferrous sulfate does not appear to increase side effects.

  • Some studies have found that the addition of zinc to iron supplements increases hemoglobin levels more than iron alone. (Some evidence for this suggests that zinc affects a hormone called insulin-like growth factor-I (IGF-I), which plays a role in the regulation of red blood cell production.)

  • A study of young Asian women found that the addition of vitamin A to iron and folate supplements increased the absorption of iron and folate. It should be noted that vitamin A is toxic in high levels and can be particularly dangerous during pregnancy. No one should take vitamin A supplements without guidance from a physician.


Intravenous or Injected Iron


In some cases iron is administered through muscular injections or intravenously. Intravenous iron has the advantage of causing less gastrointestinal discomfort and inconvenience. It may be in the form of iron dextran (Dexferrum, InFed), sodium ferric gluconate complex in sucrose (Ferrlecit), or iron sucrose (Venofer). Many experts expect that Ferrlecit or Venofer will prove to be more effective and safer than iron dextran.

Candidates. The injected or intravenous forms should be limited to the following patients with iron deficiency:

  • People with iron deficiency anemia in whom oral therapy has clearly failed.

  • Patients with bleeding disorders in which blood loss continues to exceed the rate at which oral iron is absorbed.

  • In emergencies when people need red blood cells but transfusion is not appropriate or available.

  • In people with serious gastrointestinal disorders that are severely aggravated by oral therapy.

  • People undergoing hemodialysis who receive supplemental erythropoietin therapy. Sodium ferric gluconate complex in sucrose (Ferrlecit) or iron sucrose (Venofer) is specifically approved as first-line therapy for these patients.
Certain patients, even if they meet these qualifications, may not be appropriate candidates or should be monitored closely for complications. They include:

  • Patients with any underlying autoimmune disease.

  • Malnourished patients who also have an underlying infection.

  • Patients who are at risk for iron overload.
Side Effects. Some side effects differ depending on how the iron is administered and include the following:

  • Muscular injections include pain at the site.

  • Intravenous administration can cause pain in the vein, flushing, and metallic taste, which are all brief.
For both methods side effects and serious complications can include the following:

  • Blood clots.

  • Fever.

  • Joint aches.

  • Headache.

  • Rashes.

  • Iron toxicity. Symptoms include nausea, dizziness, a sudden drop in blood pressure. Sodium ferric gluconate in sucrose (Ferrlecit) or iron sucrose (Venofer) may pose a lower risk for toxicity than iron dextran.

  • Allergic reactions. Allergic reactions that occur with intravenous iron can be very serious and, in rare cases, even fatal. Iron dextran appears to pose a much higher risk than sodium ferric gluconate complex in sucrose or iron sucrose, although allergic reactions can also occur with the latter forms.
Oral and injected iron should never be given at the same time. Intravenous iron therapy may be appropriate for some pregnant women who meet these requirements, depending on the pregnancy term and other factors.


Transfusions


If anemia is severe, transfusions may be needed. They can be essential for anemic patients who are hospitalized in the intensive care unit for their illness, particularly if they have cardiovascular disease. In fact, in a 2001 study, blood transfusions for heart attack patients with hematocrit levels below 30% were associated with higher short-term survival rates. It should be noted that if a heart attack patient's hematocrit level is above 33%, a transfusion is likely to have a negative effect and should not be performed.


Recombinant Human Erythropoietin and Intravenous Iron


Erythropoietin, the hormone that acts in the bone marrow to increase the production of red blood cells, has been genetically engineered as recombinant human erythropoietin, also called epoetin, EPO, or rHuEPO (Epogen). AraNESP is a newer version. Experts have hoped that epoetin may be helpful in certain patients with severe anemia of chronic diseases and for patients with iron deficiencies due to dialysis.

Levels of erythropoietin are reduced in ACD. Epoetin dramatically increases erythropoietin but also increases the requirements for iron. In ACD patients intravenous iron must be used as well for it to be effective. The older dextran-based IV iron is associated with some very serious side effects. The newer forms using sodium ferric gluconate complex in sucrose (Ferrlecit) or iron sucrose (Venofer) may be safer and allow a wider use of epoetin in ACD. The most effective dose of IV with the greatest safety margin is not wholly known yet. [ See Intravenous or Injected Iron under How Is Iron Deficiency Anemia Treated?]

At this point studies suggest the following use for epoetin.

  • To date, evidence on its benefits for ACD patients is strongest with its use in those who have kidney failure. In such cases, it reduces the risk of death from heart disease and improves quality of life in patients on dialysis.

  • Epoetin is also beneficial for anemia associated with severe congestive heart failure, which is now being recognized as one of the ACDs. It is proving to improve both cardiovascular function and overall health in patients with anemia and heart failure. In one study it was particularly beneficial when administered with intravenous iron.

  • Although epoetin alone is not useful for ACDs, such as rheumatoid arthritis or inflammatory bowel disease, studies are suggesting that it may be effective when used with the newer forms of intravenous iron, sodium ferric gluconate complex in sucrose (Ferrlecit) or iron sucrose (Venofer).
Epoetin in combination with iron tablets, for example, may prove to help some patients, including children, with inflammatory bowel disease who have not responded to iron and vitamin therapy alone. Some experts are also concerned that some patients may develop antibodies that react against epoetin.

Epoetin is proving to be useful for other anemias not caused by chronic diseases. [ See Box Other Uses of Recombinant Human Erythropoietin in Anemia.]


Other Uses of Recombinant Human Erythropoietin in Anemia


In addition to some cases of ACD, recombinant human erythropoietin (Epogen) is being used and investigated in the following conditions:

  • Epoetin is effective for treating cancer patients with anemia on chemotherapy.

  • Epoetin is being used to treat anemia in premature babies, but more studies are needed to determine its effectiveness over time.

  • It may improve survival and enhance the quality of life in HIV patients with anemia.

  • One European center reported that intravenous iron plus epoetin benefited severely anemic pregnant women who failed to respond to iron alone and who refused blood transfusions.



Antibiotics for H. Pylori


H. pylori , the bacteria that cause peptic ulcers, is associated with anemias from vitamin B12 deficiency and iron deficiency. In one 2000 study, eradication of H. pylori with antibiotics corrected both anemia and vitamin B12 deficiency in 40% of patients who had both conditions. Studies are also showing that the eradication of H. pylori i nfection with antibiotics can reverse anemia in patients with iron deficiency anemia and lead to long-lasting recovery.


Vitamin Replacement for Megaloblastic Anemia


Vitamin B12 Therapy. Injections of vitamin B12 (usually formulations called cyanocobalamin or hydroxocobalamin), oral folic acid therapy, or both, rapidly reverse the production of abnormally large red blood cells. (Treatments still may not reverse neurologic symptoms if they are extensive or have continued for too long.)

A typical regimen for vitamin B12 replacement is as follows:

  • If diagnostic tests indicate pernicious anemia and neurologic symptoms are present vitamin B12 therapy should begin immediately. (Usually vitamin therapy is not an emergency, however.)

  • Cyanocobalamin or hydroxocobalamin injections are given every day for up to two weeks. Only small doses are needed.

  • This is followed by injections twice a week for another month. (Hemoglobin levels rise in the first week of therapy and reach normal in eight weeks.)

  • After that, injections are usually given monthly.

  • During recovery, there is a risk of potassium deficiency as the new red cells take up the existing supply, so potassium supplements may be needed.
Other forms of Vitamin B12 are also available and can be used to treat B12 deficiency. Vitamin B12 by nasal spray offers the same advantage of avoiding the need for absorbing the vitamin in the GI tract without the inconvenience of the injections. Some experts feel that even oral B12 in high doses (2,000 mcg/day) can maintain B12 levels once the deficiency is treated.

The injections are safe and have no adverse side effects, but they may mask an underlying medical or psychological condition.

It should be noted that some physicians give vitamin B12 injections for fatigue and other vague symptoms of general mild discomfort. In one study, 10% of patients in a rural clinic were given regular B12 shots, with 6% of patients having no medical need for them.

Folic Acid Treatment. Folate deficiency is easily remedied in four to five weeks with daily oral doses of one to two milligrams of folic acid. Many doctors give vitamin B12 along with folic acid unless B12 deficiency is definitely ruled out.


WHERE ELSE CAN HELP FOR ANEMIA BE FOUND?


NIH/National Heart, Lung and Blood Institute (NHLBI) Information Center
To contact a trained information specialist at the NHLBI Information Center, Email (NHLBIinfo@rover.nhlbi.nih.gov)
Please include a valid E-mail address as well as a current postal address, since many resources are available only as printed publications. or on the Internet (https://www.nhlbi.nih.gov/index.htm)


Iron Disorders Institute Inc., P.O. Box 2031, Greenville, South Carolina 29602 Call toll-free (888-565-4766) Leave your name and how they may best reach you.
Or call (864-292-1175) or on the Internet (https://www.irondisorders.org/)


The American Academy of Pediatrics, PO Box 927, Elk Grove Village, IL 60009-0927 or on the Internet (https://www.pediatrics.org)


National Organization for Rare Disorders (NORD), P.O. Box 8923, New Fairfield, CT 06812-1783 Call (203-746-6518) or (800-999-6673) or for the hearing impaired (203-746-6927) or on the Internet (https://www.rarediseases.org/)


American Autoimmune Related Diseases Association, Inc., 22100 Gratiot Ave., Detroit, MI 48021 Call (800-776-3900) or on the Internet (https://www.aarda.org/)


Genetic Alliance, Inc., 4301 Connecticut Avenue, NW, Suite 404, Washington DC, 20008-2304 Call (800-336-GENE) or (202-966-5557) or on the Internet (https://www.geneticalliance.org/)


The Cooley's Anemia Foundation, Inc., 129-09 26th Avenue #203, Flushing, NY 11354 Call (800-522-7222) or (718-321-2873) or on the Internet (https://www.thalassemia.org)


Aplastic Anemia & MDS International Foundation of America AAFA, Inc., P.O. Box 613, Annapolis, MD 21404-0613 Call (800-747-2820) or (410) 867-0242 or on the Internet (https://www.aamds.org/)


On the Internet:
Please note: These sites are not reviewed by our physician editorial board but our writers have found them to be helpful.


This site appears to have thoughtful dietary advice (https://www.dietitian.com/iron.html)

Australian Iron Status Advisory Panel (https://www.ironpanel.org.au/)

Iron Disorders Institute (https://www.irondisorders.org/)

ConsumerLab.com (https://www.ConsumerLab.com/)
This excellent site rates supplements and alternative products according to quality and effectiveness. Their assessments now include iron supplements. The site requires a paid subscription for full access, but it is very useful.

 



 

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