FitSugar

Are You Getting Enough Iron?

FitSugar — Mon, 22 Sep 2008 12:00:00 -0700

Have you been feeling sleepy, run down, dizzy, or low in energy? Are you feeling short of breath or having a hard time focusing at work? Have you noticed that your skin is pale, or you often have headaches? It may have something to do with how much iron you're getting in your diet. An adult woman should get 18 mg of iron a day and if you're not reaching this goal, you may have iron deficiency anemia. Our bodies need iron to make hemoglobin, a substance in red blood cells that enables them to carry oxygen. If your cells aren't getting oxygen, then you'll experience the symptoms I mentioned above. You may also notice brittle nails and cold hands.

You may be at risk for low levels of iron if you tend to have heavy periods, are pregnant or just had a baby, if you are a long-distance runner, are a strict vegan, if you frequently donate blood, or if you have a gastrointestinal condition that makes it hard for you to absorb nutrients from your food. Meat, fortified cereals, dried beans, spinach, and potatoes with the skin are great sources of iron. To find how much iron they contain and see what other foods contain iron read more.

Food	Amount	Amount of Iron (in mg)
Fortified cereal	1 oz	4.5 - 7
Dried apricot	1/4 cup	1.5
Raisins	1/4 cup	1.1
Molasses	1 tbsp	3.3
Garbanzo beans	1/2 cup, cooked	3.4
Pinto beans	1/2 cup	2.2
Lima beans	1/2 cup	2.2
Lentils	1/2 cup	3.2
Soybeans	1/2 cup	7
Tofu	1/2 cup	6.2
Sun-dried tomatoes	1/2 cup	9
Spinach	1/2 cup, raw	2.7
Kale	1/2 cup, steamed	2
Broccoli	1/2 cup, raw	1
Asparagus	1/2 cup, steamed	1
Potatoes, with the skin	1/2 cup	3.2
Pine nuts	1/2 cup	9
Peanuts	1/2 cup	3.9
Pumpkin seeds	1/2 cup	14
Sunflower seeds	1/2 cup	6.7
Flaxseed	1/2 cup	6.2
Ground beef	1 patty	4
Steak	3 oz	4
Turkey (dark meat)	3 oz	4
Oysters	3 oz, steamed	7.4
Trout	3 oz	4
Shrimp	3 oz	4
Egg	1 large	.7

Fit's Tip: You can take iron supplements, but they may cause an upset stomach, heartburn, or constipation, so it's best to get your iron from foods. It's rare, but you can also get too much iron. Extra amounts of iron in the body eventually build up to dangerous levels and can cause severe damage to organs trying to store the extra iron. So be careful not to exceed your daily amount too often.

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Anemia: Know the Signs

FitSugar — Tue, 29 May 2007 03:00:00 -0700

We all get "bone" tired every now and again, but have you ever been "blood" tired? Tired blood is an expression used to explain anemia - a condition in which there isn't enough healthy red blood cells to carry adequate oxygen to your tissues - can make you feel tired. Women are more prone to suffer from anemia from men due to menstruation, pregnancy and breastfeeding.

While there are many types of anemia, iron deficiency anemia is the most common form of the problem in the U.S. affecting 1 in 5 women. Being deficient in folate and vitamin B12 can also interfere with the production of red blood cells and create anemia.

Fatigue is the primary symptom along with pale skin, irregular heartbeat and shortness of breath. If you think you might be anemic check the insides of your lower eyelids - they should be a healthy pink. If they are not, try upping your intake of iron or you can ask your doctor to give you a blood test.

Simple ways to combat anemia are eating foods rich in iron, like: red meat, fish, chicken, green leafy veggies, dried fruits (like apricots, prunes, and raisins) and lentils or beans. Up your iron intake by cooking tomato based sauces in a cast iron skillet, since acidic foods absorb the mineral from the pan. You can always try an iron supplement; just make sure it bears the United States Pharmacopeia Seal (USP).

Fit's Tip: Veteran mid-distance runner Ceci St. Geme had her last kid over 8 years ago and she still takes pre-natal vitamins because they contain iron. So keep your friends and loved ones guessing and start taking prenatal vitamins if you tend towards anemia.

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Chronic Cough? Could Be Low Iron

FitSugar — Mon, 29 Oct 2007 02:00:00 -0700

Having a chronic cough can be really annoying. The pesky throat scratching kind of cough that lingers even though you don't smoke, or have asthma or throat irritating acid reflux. Well a new study has found that having a low iron count could create a persistent cough.

Iron deficiencies and anemia can cause swelling in the back of the mouth and creating sensitive vocal cords. The heightened sensitivity, along with inflamed mucous membranes, can easily cause coughing and choking from such simple acts a vigorous laughter.

Women are more prone to iron deficiencies than our male counterparts because we menstruate monthly, which taxes our iron reserves, as does pregnancy. Taking an iron supplement can certainly help calm coughs by reducing the inflammation. Having low iron can affect your immune system since iron plays a role in the production of proteins the immune system uses to control inflammation. And that inflammation can make you more susceptible to getting sick and to coughing. It is a vicious cycle. So make sure you are getting enough iron so check out: What Your RDI of Iron Looks Like.

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Iron deficiency anemia - children

admin — Thu, 04 Sep 2008 19:19:17 -0700

Illustrations

Red blood cells, target cells

Formed elements of blood

Hemoglobin

HEALTH GUIDE REFERENCE FROM A.D.A.M

Definition

Iron deficiency anemia is a decrease in the number of red blood cells, caused by a lack of iron. This article focuses on iron deficiency anemia in children.

Alternative Names

Anemia - iron deficiency - children

Causes, incidence, and risk factors

Iron deficiency anemia is the most common form of anemia. Iron is an essential part of hemoglobin, the oxygen-carrying protein in blood. Iron comes from the diet and by recycling iron from old red blood cells.

Babies are born with about 500 milligrams (mg) of iron in their bodies. By the time they reach adulthood they need to have about 5,000 mg.

Children need to absorb an average of 1 mg per day of iron to keep up with the needs of their growing bodies. Since children only absorb about 10% of the iron they eat, most children need to ingest 8-10 mg of iron per day. Breast-fed babies need less, because iron is absorbed 3 times better when it is in breast milk.

An iron-poor diet is a common cause of iron deficiency. Drinking too much cow's milk is a common cause of iron deficiency in young children because cow’s milk contains little iron and can get in the way of iron absorption. Cow's milk also can cause problems in the intestine that lead to blood loss and increased risk of anemia.

A common time for iron deficiency is between 9 - 24 months old. All babies should have a screening test for iron deficiency at this age. Babies born prematurely may need to be tested earlier. The adolescent growth spurt is another high-risk period.

Iron deficiency in children can also be related to lead poisoning.

Symptoms

Pale skin color (pallor)
Fatigue
Irritability
Weakness
Shortness of breath
Sore tongue
Brittle nails
Unusual food cravings (called pica)
Decreased appetite (especially in children)
Headache
Blue-tinged or very pale sclerae (whites of eyes)

Note: There may be no symptoms if anemia is mild.

Signs and tests

Low hematocrit and hemoglobin levels
Small red blood cells
Low serum ferritin level
Low serum iron level
High iron binding capacity (TIBC) in the blood
Blood in stool

Treatment

Oral iron supplements are in the form of ferrous sulfate. Iron supplements are best absorbed on an empty stomach, but many people are unable to tolerate them and may need to take them with food. Milk and antacids can interfere with iron absorption and should not be taken at the same time as iron supplements. Vitamin C can increase absorption and is needed for the production of hemoglobin.

Supplemental iron is needed during pregnancy and breast-feeding because diet alone rarely supplies the needed amount.

The hematocrit should return to normal after 2 months of iron therapy, but continue taking iron supplements for another 6 to 12 months. This will replenish the body's iron stores, which are contained mostly in the bone marrow.

Intravenous or intra-muscular iron is available for people who can't tolerate oral iron supplements.

Iron-rich foods include raisins, meats (liver is the highest source), fish, poultry, egg yolks, legumes (peas and beans), and whole-grain bread.

Iron supplementation improves learning, memory, and cognitive test performance in iron-deficient adolescents. Iron supplementation also improves the performance of iron-deficient, anemic athletes.

Expectations (prognosis)

With treatment, the outcome is likely to be good. In most cases the blood counts will return to normal in 2 months.

Complications

Iron deficiency (even when not enough to cause anemia) is an important cause of decreased attention span, alertness, and learning -- both in young children and in adolescents. Iron deficiency anemia can affect school performance.

Prevention

Diet is the most important way to prevent and treat iron deficiency. Many foods are good sources of iron:

Good sources include tuna, oatmeal, apricots, raisins, spinach, kale, greens, and prunes.
Better sources include eggs, meat, fish, chicken, turkey, soybeans, dried beans, peanut butter, peas, lentils, and molasses.
The best sources are breast milk (the iron is very easily used by the child), formula with iron, infant cereals, other iron-fortified cereals, liver, and prune juice.

In addition, restrict milk to no more than 24 ounces a day. If the diet is deficient in iron, iron supplements should be taken by mouth. Your doctor may recommend increased amounts of iron during periods of increased requirements, such as teen pregnancy and breastfeeding.

References

Wu AC, Lesperance L, Bernstein H. Screening for iron deficiency. Pediatr-Rev. May 2002;23:171-178.

Review Date: 8/15/2007

Reviewed By: Rachel A. Lewis, MD, FAAP, Columbia University Pediatric Faculty Practice, New York, NY. Review provided by VeriMed Healthcare Network.

A.D.A.M., Inc. is accredited by URAC, also known as the American Accreditation HealthCare Commission (www.urac.org). URAC's accreditation program is an independent audit to verify that A.D.A.M. follows rigorous standards of quality and accountability. A.D.A.M. is among the first to achieve this important distinction for online health information and services. Learn more about A.D.A.M.'s editorial policy, editorial process and privacy policy. A.D.A.M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health on the Net Foundation (www.hon.ch).

A.D.A.M. Copyright

The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. © 1997-2009 A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.

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Source Doc: 1_007134

Iron deficiency anemia

admin — Wed, 03 Sep 2008 17:50:40 -0700

Overview

Definition
Alternative Names
Causes, incidence, and risk factors
Symptoms
Signs and tests
Treatment
Expectations (prognosis)
Complications
Calling your health care provider
Prevention

Illustrations

Reticulocytes

Blood cells

HEALTH GUIDE REFERENCE FROM A.D.A.M

Definition

Anemia is a condition where red blood cells are not providing adequate oxygen to body tissues. There are many types and causes of anemia. Iron deficiency anemia is a decrease in the number of red cells in the blood caused by too little iron. (See also Iron-deficiency anemia - children.)

Alternative Names

Anemia - iron deficiency

Causes, incidence, and risk factors

Iron deficiency anemia is the most common form of anemia. Approximately 20% of women, 50% of pregnant women, and 3% of men are iron deficient. Iron is an essential component of hemoglobin, the oxygen-carrying pigment in the blood. Iron is normally obtained through the food in your diet and by recycling iron from old red blood cells. Without it, the blood cannot carry oxygen effectively -- and oxygen is needed for the normal functioning of every cell in the body.

The causes of iron deficiency are too little iron in the diet, poor absorption of iron by the body, and loss of blood (including from heavy menstrual bleeding). It can also be related to lead poisoning in children.

Anemia develops slowly after the normal stores of iron have been depleted in the body and in the bone marrow. Women, in general, have smaller stores of iron than men and have increased loss through menstruation, placing them at higher risk for anemia than men.

In men and postmenopausal women, anemia is usually caused by gastrointestinal blood loss associated with ulcers, the use of aspirin or nonsteroidal anti-inflammatory medications (NSAIDS), or certain types of cancer (esophagus, stomach, colon).

Celiac disease may cause iron deficiency anemia.

High-risk groups include:

Women of child-bearing age who have blood loss through menstruation
Pregnant or lactating women who have an increased requirement for iron
Infants, children, and adolescents in rapid growth phases
People with a poor dietary intake of iron

Risk factors related to blood loss are peptic ulcer disease, long term aspirin use, and colon cancer.

Symptoms

Pale skin color
Fatigue
Irritability
Weakness
Shortness of breath
Sore tongue
Brittle nails
Unusual food cravings (called pica)
Decreased appetite (especially in children)
Headache - frontal
Blue tinge to sclerae (whites of eyes)

Note: There may be no symptoms if anemia is mild.

Signs and tests

Low hematocrit and hemoglobin (red blood cell measures)
Small red blood cells
Low serum ferritin
Low serum iron level
High iron binding capacity (TIBC) in the blood
Blood in stool (visible or microscopic)

Treatment

The cause of the deficiency must be identified, particularly in older patients who are most susceptible to intestinal cancer.

Oral iron supplements are available (ferrous sulfate). The best absorption of iron is on an empty stomach, but many people are unable to tolerate this and may need to take it with food. Milk and antacids may interfere with absorption of iron and should not be taken at the same time as iron supplements. Vitamin C can increase absorption and is essential in the production of hemoglobin.

Supplemental iron is needed during pregnancy and lactation because normal dietary intake rarely supplies the required amount.

The hematocrit should return to normal after 2 months of iron therapy, but the iron should be continued for another 6 to 12 months to replenish the body's iron stores, which are contained mostly in the bone marrow.

Intravenous or intra-muscular iron is available for patients who can't tolerate oral forms.

Iron-rich foods include raisins, meats (liver is the highest source), fish, poultry, eggs (yolk), legumes (peas and beans), and whole grain bread.

Expectations (prognosis)

With treatment, the outcome is likely to be good. In most cases the blood counts will return to normal in 2 months.

Complications

There are usually no complications. However, iron deficiency anemia may recur, so regular follow-up is encouraged. Children with this disorder may be more susceptible to infection.

Calling your health care provider

Call for an appointment with the health care provider if symptoms suggestive of this disorder develop or if blood is noted in the stool.

Prevention

Everyone's diet should include adequate amounts of iron. Red meat, liver, and egg yolks are important sources of iron. Flour, bread, and some cereals are fortified with iron. If you aren't getting enough iron in your diet (uncommon in the U.S.), iron supplements should be taken.

During periods of increased requirements, such as pregnancy and lactation, increase dietary intake or take iron supplements.

Review Date: 8/28/2007

Reviewed By: A.D.A.M. Editorial Team: Greg Juhn, M.T.P.W., David R. Eltz, Kelli A. Stacy. Previously reviewed by Corey Cutler, MD, MPH, FRCP(C), Assistant Professor of Medicine, Harvard Medical School; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. Review provided by VeriMed Healthcare Network (9/11/2006).

A.D.A.M. Copyright

adam.com

Source Doc: 1_000584

Anemia

FitSugar — Wed, 08 Oct 2008 17:34:56 -0700

In This Report

Highlights
Introduction
Causes
Risk Factors
Complications
Symptoms
Diagnosis
Dietary Factors
Treatment
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

FDA Issues Labeling Changes for Drugs That Boost Red Blood Cells

In November 2007, the U.S. Food and Drug Administration (FDA) made several changes to the prescribing labels for erythropoiesis-stimulating drugs. These drugs -- epoietin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp) -- increase the production of red blood cells. They are used to treat anemia associated with chronic kidney failure, cancer chemotherapy, and antiretroviral HIV therapy.

The new labels have stronger warnings and updated dosing-related safety information. The FDA advises:

For cancer, erythropoiesis-stimulating drugs are used only to treat anemia associated with chemotherapy. Dosing should increase hemoglobin levels to no more than 12 g/dL. These drugs can shorten survival time and increase tumor growth when hemoglobin levels are raised beyond this point. Treatment should stop as soon as chemotherapy is completed. Erythropoiesis-stimulating drugs are not safe or appropriate for all patients undergoing chemotherapy. Patients should discuss the risks and benefits with their oncologists.
For chronic kidney failure, erythropoiesis-stimulating drugs should be used to maintain a hemoglobin level between 10 - 12 g/dL. Higher hemoglobin levels increase the risk for stroke, heart attack, heart failure, or death.
Erythropoiesis-stimulating drugs are used to increase red blood cell numbers and reduce the need for blood transfusions. They do not help improve anemia symptoms, fatigue, or quality of life for patients with cancer or HIV.
Patients who take these drugs should contact their doctors if they experience symptoms such as leg pain or swelling, increased shortness of breath, increased blood pressure, dizziness, or extreme fatigue.

Introduction

Anemia is an abnormal reduction in red blood cells.

This photmicrograph shows normal red blood cells (RBCs) as seen in the microscope after staining.

Anemia is a global problem, at its worst in developing countries. But it is by no means absent in industrialized nations. An estimated 3.4 million Americans suffer from anemia. Anemia is not a single disease but a condition, like fever, with many possible causes and many forms. Causes of anemia include nutritional deficiencies, inherited genetic defects, medication-related side effects, and chronic disease. It can also occur because of blood loss from injury or internal bleeding, the destruction of red blood cells, or insufficient red blood cell production. The condition may be temporary or long-term, and can manifest in mild or severe forms.

As it is impossible to discuss all types of anemia, this report focuses on three of the most common forms:

Iron deficiency anemia
Anemia of chronic disease (ACD)
Megaloblastic anemia (caused by deficiencies in the B vitamins folate, vitamin B12, or both)

Some less common causes and types of anemia are included in a table in this report.

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 (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 5.2 million red blood cells per cubic millimeter of blood, and women have about 4.7 million per cubic millimeter of blood.

Hemoglobin and Iron

Each red blood cell contains 200 - 300 hemoglobin molecules. Hemoglobin is a complex molecule, and it is the most important component of red blood cells. It is composed of protein (globulin) and a molecule (heme), which binds to iron.

In the lungs, the heme component binds to oxygen in exchange for carbon dioxide. 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.

Red blood cells typically circulate for about 120 days before they are broken down in the spleen. Most of the iron used in hemoglobin can be recycled from there and reused.

Structure and Shape of Red Blood Cells

Red blood cells -- the erythrocytes -- 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.

Abnormally shaped or sized erythrocytes are typically destroyed and eliminated.

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 5 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 needs more 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 lifespan of a red blood cell is 90 - 120 days. The liver and the spleen remove old red blood cells are removed from the blood by the liver and spleen.
When old red blood cells are broken down for removal, iron is returned to the bone marrow to make new cells.

Click the icon to see an image of the formed elements of blood.

Click the icon to see an image of hemoglobin.

Causes

Iron deficiency anemia occurs when the body lacks mineral iron to produce the hemoglobin it needs to make red blood cells. In general, there are three stages leading from iron deficiency to anemia:

First, there is an insufficient supply of iron, which causes iron stores in the bone marrow to be depleted. This stage generally has no symptoms.
Second, iron deficiencies develop and begin to affect hemoglobin production. (Tests will show low hemoglobin and hematocrit levels.)
Hemoglobin production declines to the point where anemia develops.

Most of the iron used in the body can be recycled from blood and reused. Nevertheless, iron deficiency can occur from a number of conditions.

Inadequate Iron Intake. A healthy diet easily provides enough iron. In general, most people need just 1 mg, and menstruating women need 2 mg of extra iron each day. This means that lack of iron in the diet is not a common cause of iron deficiency anemia, except in infants. In fact, most American adults may be consuming too much iron in their diet. Most of the iron in red blood cells is recycled and reused. Iron-poor diets are a cause of anemia only in people with existing risks for iron deficiency. Children who have not yet eaten iron-fortified formulas or iron-enriched cereal may also become anemic.

Blood Loss. Iron deficiencies most commonly occur from internal blood loss due to other conditions that range in severity. These conditions include:

Peptic ulcers, which may be caused by H. pylori infections, or aspirin and drugs or nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen. About 70% of long-term users of these medications have some sign of gastrointestinal bleeding, although it is rarely significant enough to cause anemia.
Duodenal ulcers
Hemorrhoids
Colon polyps
Colon, stomach, and esophageal cancer
Very heavy periods (menorrhagia) are the most common causes of anemia in premenopausal women.
Bleeding from esophageal varices, often present in alcoholics

Impaired Absorption of Iron. Impaired absorption of iron is caused by:

Certain intestinal diseases (inflammatory bowel disease, celiac disease)
Surgical procedures, particularly those involving removal of parts of the stomach and small intestine, can impair the ability of the stomach or intestine to absorb iron. (Such conditions also often impair folic acid absorption as well.)
Pica, the craving for non-food substances such as ice, starch, or clay, is a possible cause of iron deficiency. To complicate matters, pica (particularly ice cravings) may also be a symptom, rather than a cause, of anemia.
Certain intestinal infections, such as hookworm and other parasites.

Click the icon to see an image of inflammatory bowel disease.

Genetic Causes. Some people are born with iron deficiency. Certain 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), also called anemia of chronic inflammation (ACI), is a common condition associated with a wide variety of persistent inflammatory diseases. It can be very severe and require transfusions.

The Inflammatory Process and ACD. ACD is not completely understood. In ACD, iron is not efficiently recycled from blood cells, and red blood cell survival is reduced. In addition, there is impaired response to erythropoietin, the hormone that acts in the bone marrow to increase the production of red blood cells. (Abnormal function and low levels of erythropoietin, in fact, may be the most important factor in ACD, with iron insufficiencies being a consequence.)

The process leading to ACD may occur in the following way:

The immune system activates white blood cells and releases various compounds during times of infection that are intended to fight invaders and heal wounds. Such an event causes an inflammatory state in the areas of the attack.
White blood cells called macrophages release small but powerful proteins known as cytokines, which are critical in the development of ACD. Cytokines are indispensable for healing. However, cytokines are overproduced often in chronic and inflammatory diseases, causing serious tissue injury and, in some cases, even organ damage. In the case of ACD, they prevent production of erythropoietin, the hormone that acts in the bone marrow to increase the production of red blood cells. Specific cytokines implicated in anemia are interleukin 1 (IL-1), tumor necrosis factor (TNF), and interferons.
As part of this process, mechanisms prevent the release of recycled iron needed in the bone marrow for the manufacturing of red blood cells. Iron absorption in the intestines is also blocked. Theoretically, this is a protective measure, since iron may help infectious organisms proliferate. In such cases, iron stores are high, but the usable iron in circulation is low.
Researchers have identified a peptide called hepcidin, which prevents iron absorption in the intestine and blocks the release of iron by immune factors for red blood cell production. Some experts believe high levels of the peptide may play a central role in preventing the release of iron during infection and inflammatory states, and is critical in ACD.

Diseases Associated with ACD and Inflammation. The chronic diseases that are associated with this process include:

Certain cancers. Examples include lymphomas and Hodgkin's disease.
Autoimmune diseases. Examples include rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, and polymyalgia rheumatica.
Long-term infections. Examples include chronic or recurrent urinary tract infections and osteomyelitis.
Hepatitis C. The liver cirrhosis associated with hepatitis C can reduce the production of red blood cells. Gastrointestinal bleeding may also contribute to blood loss.
Heart failure. Experts estimate that 25 - 60% of patients with heart failure also have anemia. However, it is unclear whether anemia actually causes or worsens heart failure. Recent research suggests it may actually be a sign (marker) of heart failure. Iron deficiency in heart failure can be due to a number of factors. It may be caused by a lack of nutrients in a person’s diet or by the body’s inability to absorb nutrients from food. Heart failure can also cause a back up of fluid (edema). This edema produces a higher volume of blood plasma (the liquid part of blood), which can dilute red blood cells and cause anemia.
Chronic kidney disease. The hormone erythropoietin (EPO) is produced in the kidneys and stimulates the bone marrow production of red blood cells. Diseased kidneys do not release sufficient amounts of EPO; anemia can result and is universal in end-stage renal disease. Chronic kidney disease is a common complication of diabetes.
HIV/AIDS. The inflammatory process associated with AIDS can adversely affect EPO levels and red blood cell production.
Anemia in critically ill patients. Evidence suggests similarities between ACD and severe anemia in patients who are in intensive care. Some experts believe that the cause of anemia in such critically ill patients may also be due to inflammatory responses that promote impaired responsiveness to erythropoietin.

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.

Treatment-Related Anemia. Anemia can also result from the therapies used to treat conditions. For example, anemia is a common side effect of cancer treatments. Chemotherapy and radiation can impair the bone marrow's production of red blood cells and contribute to the extreme fatigue that many patients experience during cancer therapy. Patients with hepatitis C frequently receive combination therapy of ribavirin and interferon; ribavirin can induce anemia. Hepatitis C also affects many patients with HIV or AIDS. In addition to ribavirin, patients with HIV or AIDS can develop anemia as a result of highly active anti-retroviral therapy (HAART) and, in particular, from the drug AZT.

Other medications that increase the risk for anemia are certain antibiotics, some antiseizure medications (phenytoin), immunosuppressive drugs (methotrexate, azathioprine), antiarrhythmic drugs (procainamide, quinidine), and anti-clotting drugs (aspirin, warfarin, heparin).

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

Click the icon to see an image of red blood cells seen in megaloblastic anemia.

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

Vitamin B12 deficiency from diet is very rare, since the liver stores over a 3-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
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 age 60, with women having a higher risk than men.
Complications of gastrointestinal surgery. Surgeries such as stomach bypass or stapling, which remove part or all of the stomach, pose a 15 - 30% chance of causing vitamin B12 deficiencies.
Overgrowth of intestinal bacteria
Tropical sprue (an acquired malabsorption disease occurring in tropical climates)

Click the icon to see an image of the benefits of vitamin B12.

Causes of Folate Deficiency. The body stores only about 100 times its daily requirements for folate and can exhaust this supply within about 3 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 also 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 inflammatory bowel disease or celiac sprue (a sensitivity reaction to gluten)

Click the icon to see an image of foods that contain gluten.

Parasitic diseases such as giardiasis
Short bowel syndrome
Deficiencies can also arise due to high demand for folic acid caused by conditions such as cancer, pregnancy, severe psoriasis, severe hyperthyroidism, and hemolytic anemia.
Some drugs, including phenytoin, methotrexate, trimethoprim, and triamterene, may also hinder folate absorption.


Form of Anemia	Description and Diagnosis	Causes and Risk Factors	Treatments
Aplastic Anemia	Bone marrow fails to produce all types of blood cells. Symptoms, in addition to standard anemia, are bleeding in mucous membranes and skin, gingivitis, higher risk for infection, and shortness of breath.	Cause is unknown in half the cases. Known causes include hereditary conditions (Fanconi's anemia), viruses (HIV, hepatitis, Epstein-Barr), autoimmune diseases (lupus, rheumatoid arthritis), medications (valproic acid, tacrolimus, azathioprine) or chemicals (benzene, pesticides).	Transfusions, antibiotics, bone marrow or stem cell transplantation, immunosuppressant drugs. (This anemia used to be nearly always fatal, but survival rates now can reach 92% with successful transplants and up to 87% with immunosuppressants.)
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 lifespan 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.	Transfusions to supply enough red blood cells to achieve moderate anemia and avoid iron overload are standard approaches for thalassemia major. Investigations are ongoing to find alternatives to transfusions. Hydroxyurea, 5-azacytidine, erythropoietin, or butyrate analogues may help some patients. Bone marrow transplantation may be needed for some types of thalassemia.
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, lymphoma, and paroxysmal nocturnal hemoglobinuria. Other causes are high exposure to certain metals or chemicals (lead, copper, benzene, naphthalene), snake and insect bites, malaria, transfusions, post-surgical complications, and drugs such as methyldopa. In infants, blood group incompatibility between mother and child or infections in the womb.	Corticosteroids for autoimmune hemolytic anemia. Transfusions beneficial in many cases. Various immunosuppressive drugs may be tried, as well as splenectomy. Eculizumab (Soliris) is approved for treatment of paroxysmal nocturnal hemoglobinuria.
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) or bone marrow transplantation 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 lifespan 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. [For information, see In-Depth Report #58: Sickle-cell disease.]

Click the icon to see an image of red blood cells found in sickle cell anemia.

Risk Factors

Although nutritional iron-deficiency anemia has declined in industrialized nations, it affects an estimated 2 billion people worldwide. Even in the U.S., iron deficiency is the most prevalent nutritional deficiency. It is highly associated with poverty. People in lower socioeconomic groups have double the risk of those who are middle or upper class.

Among Americans with iron deficiency anemia, young children have the highest risk followed by premenopausal women. 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.

General Risk Factors for Anemia in Infants and Children. Up to 20% of American children and 80% of children in developing countries become anemic at some point during their childhood and adolescence. Iron deficiency is the most common cause in children, but other forms of anemia, including hereditary blood disorders, can also cause anemia in this population. Hispanic American children have double the rates of iron deficiency as African-American and Caucasian children.

Iron deficiency affects about 9% of children younger than 2 years. About 3% of children in this age group are anemic as a result. Children in lower-income homes are at higher risk than those in higher income homes. In a study of low-income children, ages 6 months to 5 years, the prevalence of anemia was over 10%, and was nearly 18% in children younger than 2 years. However, children in any income group can develop iron deficiency.

Young children 9 - 18 months have the highest risk for iron deficiency anemia in the U.S. Such children also are at great risk for problems in mental development from anemia. Infant boys may have 10 times more risk than baby girls. In general, full-term, breast-fed infants have enough iron stores for their first 6 months of life. After that, they must rely on other sources for iron.

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

Stopping breast-feeding too early or using formula that isn't iron-fortified.
Bottle-feeding too long. Studies indicate that the longer children are bottle-fed, the greater the risk for iron-deficiency and anemia. Toddlers 12 months and older should not drink more than 2 cups of milk a day. Cow’s milk is good for children, but it does not contain enough iron. Too much milk can decrease children’s appetite and prevent them from eating the iron-rich food they need. When babies who are bottle-fed are 7 - 9 months old, they should be weaned from bottles and given sippy cups. By the age of 12 months, all children should be using a cup instead of a bottle.
Toddlers’ preferences for iron-poor food. Parents should make sure that their children eat iron-rich foods, such as beans, meat, fortified cereals, eggs, and green leafy vegetables

Better social services and more accurate ways of diagnosing and monitoring anemia are needed in these high-risk groups. There is still considerable debate on how to define iron deficiency and anemia in infants. New research suggests that a reticulocyte hemoglobin content (CHr) test may be better than a standard hemoglobin test for detecting iron deficiency in babies. Reticulocytes are immature red blood cells. The CHr test measures the amount of hemoglobin in these cells.

Up to 10% or more of adolescent and adult women under 49 years are iron deficient. Hispanic American and African-American women have double the prevalence for anemia compared to Caucasian women. The risk for anemia in adolescent girls is about 3%. Anemia is generally mild in young women, however, and is more likely to occur with one or more of the following conditions:

Heavy menstruation for longer than 5 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.

Although studies have reported various estimates on the prevalence of anemia in older adults, one survey suggested that anemia affects about 10% of adults aged 65 years and older, and more than 20% aged 85 years and older. The causes of anemia in older adults were equally distributed among nutritional deficiencies, chronic inflammatory disease, chronic renal disease, and unexplained anemia. Most cases were mild.

People with alcoholism are at risk for anemia both from internal bleeding as well as folate- and vitamin B deficiency-related anemias.

Although most Americans probably consume too much iron in their diets, some people may be at risk for diet-related iron deficiencies, including:

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).

Anyone with a chronic disease that causes inflammation or bleeding is at risk for anemia. Critical illness in the intensive care unit is also highly associated with anemia.

Working out regularly may cause some iron loss, which is comparable to that from menstruation and rarely worrisome. 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.

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 30 - 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:

It 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.
It increases the body's demand for iron, thus posing a risk for iron deficiency anemia. Pregnant or nursing women need 30 mg of iron per day. Maternal iron deficiency anemia is associated with increased weight or size of the placenta, a condition that may later pose a risk for 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.
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 - 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. Researchers are also investigating Doppler ultrasonography as an imaging technique for detecting anemia in the fetus. Traditionally, fetal anemia is diagnosed through amniocentesis. Doppler ultrasonography is a non-invasive method that does not risk causing a miscarriage or a worsening of fetal anemia.

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 most pregnant women experience is harmful. In addition, iron supplements cause gastrointestinal side effects and may not be completely harmless. Some experts suggest iron supplements for all pregnant women whose hemoglobin levels are less than 11 g/dl, and pregnant women whose serum ferritin levels are low, beginning in their 20th - 24th weeks of pregnancy.
Vitamin 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. Folate is the natural form of folic acid, but 400 mcg supplements of folate are half as potent as the same dose of folic acid. Pregnant and nursing women who are vegetarians should be sure to have supplements of folic acid and other B vitamins as well, since many of these nutrients are found primarily in animal products. Vitamin B12 deficiencies during pregnancy can also produce anemia in both mother and child.
Diets Rich in Vitamin C. Eating foods rich in vitamin C can help absorb iron.

Treating Anemia During Pregnancy. Pregnant women who become anemic and need treatment may be given oral iron supplements, or blood transfusions in severe cases. Intravenous or intramuscular administration of iron helps improve blood levels better than oral iron supplements, but may cause more serious side effects.

Complications

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.

Because a reduction in red blood cells decreases the ability to absorb oxygen from the lungs, 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 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.

Pregnant women with significant anemia may have an increased risk for poor pregnancy outcomes, particularly if they are anemic in the first trimester.

In children, severe anemia can impair growth and motor and mental development. Children may exhibit a shortened attention span and decreased alertness. Children with severe iron-deficiency anemia may also have an increased risk for stroke.

Anemia is common in older people and can have significantly more severe complications than anemia in younger adults. Some studies have reported higher mortality rates in anemic individuals 85 and older compared to their non-anemic peers. (The rates were higher in anemic men than in women.) The following are examples of its effects from different studies:

Anemia may have adverse effects on the heart and increase the severity of cardiac conditions, including reducing survival rates from heart failure and heart attacks.
Elderly people with lower levels of hemoglobin are at an increased risk of death.
Anemia may be associated with an increased incidence of falls.
Even mild anemia may possibly lead to cognitive impairment. A 2006 study of elderly women found that mild anemia worsened problem-solving abilities and other cognitive functions. Anemia may worsen an already existing dementia.

In addition to anemia, vitamin B12 deficiency can cause neurologic damage, which can be irreversible if it continues for long periods without treatment.

Anemia is particularly serious in cancer patients. In people with many common cancers, the presence of anemia is associated with a shorter survival time.

Anemia is associated with higher mortality rates and possibly heart disease in patients with kidney disease.

The combination of anemia and heart failure can increase the risk of hospitalization or death by 30 - 60%. Patients with heart failure whose hemoglobin levels decline do worse than patients with stable levels.

Blood transfusions. Patients with certain types of anemia require frequent blood transfusions. These transfusions can cause iron overload. Patients are treated with iron chelation therapy, which uses a drug that binds to iron. Excess iron is then eliminated by the kidneys. The standard drug for iron chelation therapy, deferoxamine (Desferal), is injected intravenously through an infusion pump. The treatment can be difficult for many patients. In 2005, the FDA approved a new drug, deferasirox (Exjade), to treat iron overload due to blood transfusions. Patients dilute the pills in liquid once a day and drink the mixture.

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:

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 (however, healthy-looking skin color does not rule out anemia if a patient has risk factors and other symptoms of anemia)
Mental confusion
Loss of sexual drive

Pica. One odd symptom, 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 2 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 when angry or upset, even to the point of fainting, may be iron-deficient. In one study, taking iron supplements reduced this phenomenon in 88% of treated children.

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

Inflammation of the mouth (stomatitis)
Inflammation of the tongue (glossitis), which involves shrinkage at the surface and edges of the tongue

Over time, psychiatric and neurologic problems develop. Vitamin B12 deficiencies cause neurologic symptoms (numbness and tingling, depression, memory loss, and irritability), and folate deficiency may result in depression and dementia (in severe cases).

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. The only cure is vitamin B12 supplementation.

Diagnosis

The first step in any diagnosis is a physical examination to determine if the patient has symptoms of anemia and any complications. 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 factors. A detailed medical, personal, and dietary history should report:

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 be present, so a rectal exam and stool test are essential.)
Any dietary history, particularly in people who are elderly, poor, or both

The doctor should examine the patient carefully, especially checking for swollen lymph nodes, an enlarged spleen, and pale skin and nail color.

Specific blood tests are given to determine anemia from any cause.

Blood and Hemoglobin Counts. A complete blood count (CBC) test is 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:

Hemoglobin concentrations below 12 g/dL (7.5 mmol/L) in women. (Some evidence suggests that in older women anemia should be diagnosed at 13 g/dL and below.)
Below 13 g/dL (8.1 mmol/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 - 60%
Children: 35 - 45%
Adult males: 41 - 53%
Adult women: 36 - 46%

Normal value ranges may vary slightly among different laboratories.

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, heart failure, and 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. New research suggests that the reticulocyte hemoglobin content (CHr) test may be more accurate than a standard hemoglobin test for detecting iron deficiency in infants. This test may help identify babies who are at risk for becoming anemic and help them get treated earlier.

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

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.

There are two steps in making a 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, 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 (hypochromic) and abnormally small (microcytic). They are also mostly uneven in shape. (These findings suggest iron deficiency, but they can also appear in cases of anemia due to chronic disease and thalassemia.)
Hemoglobin and iron levels are low. (These findings further suggest iron deficiency, but they can also occur in cases of anemia due to chronic disease.)
Ferritin levels are low. Ferritin is a protein that binds to iron. Low levels typically mean reduced iron stores. High ferritin levels in the blood do not always mean sufficient iron stores. For example, pregnant women may have high ferritin levels into their third trimester but still be iron deficient. Ferritin levels may also be normal or even elevated in patients with inflammation from anemia due to chronic disease, even if they also have low iron stores.
In children with iron deficiencies, reticulocytehemoglobin levels are low. Reticulocytes are immature red blood cells, and this test may be the most effective approach for diagnosing iron deficiency in children.
A test that measures a factor called serum transferrin receptor (TfR) is proving to be very sensitive in identifying iron deficiency in problematic patients, including the elderly with chronic diseases and possibly pregnant women. (It is often very difficult to identify iron deficiencies in patients who also have anemia due to chronic diseases because their ferritin levels are often normal or even high.) For example, levels of TfR are high in patients with ACD and iron deficiency anemia, but they are normal or only slightly raised in ACD alone. The test is expensive, however, and some experts recommend it should be used only when there is a high suspicion of iron deficiency in the elderly.
Measuring erythrocyte zinc protoporphyrin (ZPP), a product of abnormal heme synthesis, is under investigation and may prove to be a simple and precise measure of iron deficiencies, particularly in children.

If internal bleeding is suspected as the cause, the gastrointestinal tract is usually the first suspect as the source. A diagnosis in these cases can often be made if the patient has noticed blood in the stools, which can be black and tarry or red-streaked. Often, however, bleeding may be present but not visible. If so, stool tests for this hidden (occult ) blood are required. Additional tests may then be needed to diagnose the precipitating condition. Endoscopy, in which a fiber optic tube is used to view into the gastrointestinal tract, is helpful in many patients, particularly when the source of bleeding is unclear. A colonoscopy may also be recommended to rule out colorectal cancer.

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.

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.)

Doctors need a multi-step diagnostic procedure for determining vitamin B deficiencies and the anemias that cause or are caused by them. Doctors 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 doctor 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.

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 doctor has not found any intestinal abnormalities or other factors to account for the deficiency, the doctor presumes a diagnosis of pernicious anemia. Pernicious anemia may also be diagnosed through various blood (such as complete blood count) or urine tests.

Pernicious anemia is treated with vitamin replacement, but the condition 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.

Dietary Factors

Iron found in foods is either in the form of heme or non-heme iron:

Heme Iron. Foods containing heme iron are the best sources for increasing or maintaining healthy iron levels. Such foods include (in decreasing order of iron-richness) clams, oysters, organ meats, beef, pork, poultry, and fish.
Non-Heme Iron. Non-heme iron is less well-absorbed. About 60% of the iron in meat is non-heme (although meat itself helps absorb non-heme iron). Eggs, dairy products, and iron-containing vegetables have only the non-heme form. Such vegetable products 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.

The absorption of non-heme iron often depends on the food balances in meals. The following foods and cooking methods can enhance absorption of iron:

Meat and fish not only contain heme iron -- the best form for maintaining stores -- but they also help absorb non-heme iron.
Increasing intake of vitamin-C rich foods, such as orange juice, may enhance absorption of non-heme iron, although it is not clear if it improves iron stores in iron-deficient people. In any case, vitamin-C rich foods are healthy and include broccoli, cabbage, citrus fruits, melon, tomatoes, and strawberries.
Riboflavin (vitamin B2) may help enhance the response of hemoglobin to iron. Food sources include dairy products, liver, and dried fortified cereals.
Cooking methods can enhance iron stores. Cooking in cast iron pans and skillets is well-known to increase the iron content of food. According to one study, boiling, steaming, or stir-frying in utensils composed of any material significantly increased the release of non-heme iron stored in vegetables.
Vitamins B12 and folate are important for prevention of megaloblastic anemia and for 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). As is the case with other B vitamins, however, B12 is added to commercial dried cereals. The recommended daily allowance (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.

Click the icon to see an image of sources of vitamin B12.

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 -- considerably higher than standard recommendations of 400 mcg of folate. Women who are trying to conceive, who are pregnant, and who are breast-feeding should take 400 mcg of folic acid.

Click the icon to see an image of sources of folate.

The Recommended Daily Allowance (RDA) 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.) The RDA recommends these daily amounts of iron:

Children 1 - 3 years old: 10 mg
Teenage boys: 12 mg
Teenage girls and premenopausal women: 15 mg
Pregnant or nursing women: 30 mg
Adult men (up to age 50): 10 mg
Older men and women (over age 50): 10 mg

The main source of iron for an infant from birth to 1 year of age is in milk, from breast milk, iron-fortified infant formula, or cereal. The best methods for preventing iron deficiency during infancy are:

Breast-feeding and Iron-Supplemented Formulas. Mothers should be encouraged to breast-feed their babies for their first year. Up to half of the iron in breast milk is absorbed by the baby and is sufficient to prevent anemia for the first 4 - 6 months, assuming that the mother had adequate iron stores during pregnancy. 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. Breast-fed babies should have iron supplements after 4 - 6 weeks, even if they are still nursing.

Infants who are not breast-fed should start with iron-fortified formulas (7-12 mg/L). Most experts strongly discourage the use of low-iron formulas (less than 4.0 mg/L). Parents should discuss the best formula with their doctor. Children given iron supplements may have a slightly higher risk for diarrhea. Experts advise against cow's milk for the first year of life. When cereals are begun, they should be iron fortified.

Recommendations for Toddlers. Toddlers who did not have iron supplements during infancy should be checked for iron deficiency. After the first year, children should be given a varied diet that is rich in sources of iron, B vitamins, and vitamin C. Milk does not contain enough iron and can decrease children's appetite for iron-rich foods. Toddlers older than 1 year should not drink more than 2 cups of milk a day. A preference for apple juice over vitamin-C rich orange juice does not reduce iron absorption in children with any otherwise healthy diet.

Treatment

Oral iron supplements are the best way to restore iron levels for people who are iron deficient, but they should be used only when dietary measures have failed. However, iron supplements cannot correct anemias that are not due to iron deficiency.

One study reported that doctors 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. Experts generally advise against iron supplements in anyone with a healthy diet and no indications of iron deficiency anemia. However, one study suggested that supplements help reduce fatigue in women with low iron stores but no signs of 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 used for some patients.

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

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, doctors 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 are still absorbed but with fewer side effects.)
Always drink a full 8 ounces of fluid with an iron pill. Taking orange juice with an iron pill may help increase iron absorption. (Some doctors also recommend taking a vitamin C supplement with the 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.)

Full recovery takes 6 - 8 weeks. Recovery will take longer in people with internal bleeding that is not under control. Iron replacement therapy must continue for about 6 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 doctor 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 Parkinson's disease drugs methyldopa, levodopa, and carbidopa. At least 2 hours should elapse between doses of these drugs and iron supplements.

Supplements. The following vitamin and mineral supplements may improve iron absorption:

Adding either ascorbic acid (vitamin C) or succinic acid to ferrous sulfate therapy will improve absorption of iron stores.
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.

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). Ferrlecit or Venofer are proving to be at least equally 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, such as inflammatory bowel disease, who cannot take iron therapy by mouth.
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, all of which are brief.

For both methods, side effects and serious complications can include:

Blood clots
Fever
Joint aches
Headache
Rashes
A delayed reaction of joint and muscle aches, headache, and malaise occurs 1 - 2 days after the infusion (most commonly with iron dextran) in about 10% of patients. These symptoms respond quickly to NSAIDs, such as ibuprofen or naproxen, in most people.
Iron toxicity. Symptoms include nausea, dizziness, and 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 are used to replace blood loss due to injuries and during certain surgeries. They are also commonly used to treat severely anemic patients who have thalassemia, sickle cell disease, myelodysplastic syndromes, or other types of anemia. Some patients require frequent blood transfusions. Iron overload can be a side effect of these frequent blood transfusions. If left untreated, iron overload can lead to liver and heart damage.

Iron chelation therapy is used to remove the excess iron caused by blood transfusions. Patients take a drug that binds to the iron in the blood. The excess iron is then removed from the body by the kidneys. For many years, deferoxamine (Desferal) was the only drug used in chelation therapy. This drug is usually injected intravenously, using an infusion pump. The infusion can last 8 - 12 hours and may be needed 5 - 7 days a week until iron levels are normal. A new drug, deferasirox (Exjade), was approved in 2005 for children and adults as a once-daily treatment for iron overload due to blood transfusions. It does not require injections. Patients mix the deferasirox tablets in liquid and drink the medicine. Doctors hope that this new drug may make it easier for patients to tolerate chelation therapy. Studies have shown that deferasirox works as well as deferoxamine in ridding the body of excess iron.

Bloodless Medicine. Bloodless medicine and surgery is a new field designed to reduce or minimize blood loss and transfusions. It also attempts to address the problems in treating certain religious groups, such as Jehovah's Witnesses, who refuse transfusions. Some techniques involved in this field include new surgical procedures or drugs that minimize blood loss, the use of erythropoietin, volume expanders (administration of fluids to dilute blood), using tiny blood samples for testing, and methods (Cell Saver) for recovering and recycling blood during surgery.

Erythropoietin is the hormone that acts in the bone marrow to increase the production of red blood cells. It has been genetically engineered as recombinant human erythropoietin (rHuEPO) and is available as epoetin alfa (Epogen, Procrit, and Eprex). Novel erythropoiesis stimulating protein (NESP), also called darbepoetin alfa (Aranesp), lasts longer in the blood than epoetin alfa and requires fewer injections. These medications are also called “erythropoiesis-stimulating drugs.”

Levels of erythropoietin are reduced in anemia of chronic disease. Injections of synthetic erythropoietin can help increase the number of red blood cells in order to avoid receiving blood transfusions. Erythropoietin is used to treat anemia. It does not help improve anemia symptoms, fatigue, or quality of life for patients with cancer or HIV. This drug can cause serious side effects, including blood clots, and is approved only for treating patients with anemia related to the following conditions:

Cancer. For select patients, erythropoietin is used to treat the anemia associated with chemotherapy.
Chronic kidney failure. Erythropoietin is an important anemia treatment for patients with chronic kidney failure, including those on dialysis.
HIV/AIDS. Erythropoietin helps treat the anemia caused by zidovudine (AZT) therapy.

In November 2007, the Food and Drug Administration (FDA) made major changes to the prescribing information for erythropoiesis-stimulating drugs. The new labels describe in detail the risks that Aranesp, Epogen, and Procrit can pose to patients with cancer and chronic kidney disease. The FDA has also established separate dosing recommendations for each of these conditions.

Erythropoiesis-Stimulating Drugs and Cancer. Erythropoietin should be used only to treat anemia caused by chemotherapy -- not anemia due to other causes in patients with cancer. Erythropoietin treatment does not help prolong survival. In fact, these drugs can shorten survival time and cause tumors to grow faster. Discuss with your doctor whether an erythropoiesis-stimulating drug is appropriate for you.

Survival and tumor growth risks are especially pronounced for patients with advanced breast, head and neck, lymphoid, or non-small cell lung cancer when dosing attempts to achieve a hemoglobin level of 12 g/dL or greater. However, there may be similar risks for patients dosed to less than 12 g/dL. (The American Society of Clinical Oncology and the American Society of Hematology recommend starting erythropoietin when a patient’s hemoglobin level falls to less than 10 g/dL.) The doctor should use the lowest effective dose and erythropoietin treatment should be stopped as soon as the chemotherapy course is completed.

Erythropoiesis-Stimulating Drugs and Chronic Kidney Failure. For patients with chronic kidney failure, the FDA recommends that erythropoiesis-stimulating drugs be used to maintain hemoglobin levels between 10 - 12 g/dL. (The exact level within this range varies by individual.) There is a greater risk of death and serious cardiovascular events, such as heart attack, stroke, and heart failure when these drugs are used to achieve higher hemoglobin levels (13.5 - 14g/dL) compared to lower hemoglobin levels (10- 11.3 g/dL).

Warning Symptoms. Contact your doctor if you experience any of the following symptoms while being treated with an erythropoiesis-stimulating drug:

Pain or swelling in the legs
Worsening in shortness of breath
Increases in blood pressure (be sure to regularly monitor your blood pressure)
Dizziness or loss of consciousness
Extreme fatigue
Blood clots in hemodialysis vascular access ports

H. pylori, the bacteria that cause peptic ulcers, is associated with anemias from vitamin B12 deficiency and iron deficiency. People whose anemia is associated with H. pylori infection, however, do not respond to iron therapy. Studies indicate that the eradication of H. pylori infection with antibiotics can reverse anemia in such patients and may lead to long-lasting recovery.

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 2 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 levels in 8 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 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.

Some doctors 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 4 - 5 weeks with daily oral doses of 1 - 2 milligrams of folic acid. Many doctors give vitamin B12 along with folic acid unless B12 deficiency is definitely ruled out.

Resources

www.anemia.org -- National Anemia Action Council
www.nhlbi.nih.gov -- National Heart, Lung and Blood Institute
www.irondisorders.org -- Iron Disorders Institute
www.thalassemia.org -- Cooley's Anemia Foundation
www.aamds.org -- Aplastic Anemia & MDS International Foundation
http://kidney.niddk.nih.gov/kudiseases/pubs/anemia -- National Kidney and Urologic Diseases Clearinghouse (Anemia in kidney disease and dialysis)

References

Brotanek JM, Gosz J, Weitzman M, Flores G. Iron deficiency in early childhood in the United States: risk factors and racial/ethnic disparities. Pediatrics. 2007 Sep;120(3):568-75.

Killip S, Bennett JM, Chambers MD. Iron deficiency anemia. Am Fam Physician. 2007 Mar 1;75(5):671-8.

Komajda M, Anker SD, Charlesworth A, et al. The impact of new onset anaemia on morbidity and mortality in chronic heart failure: results from COMET. Eur Heart J. 2006 Jun;27(12):1440-6. Epub 2006 May 22.

KDOQI. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis. 2007 Sep;50(3):471-530.

Maguire JL, deVeber G, Parkin PC. Association between iron-deficiency anemia and stroke in young children. Pediatrics. 2007 Nov;120(5):1053-7.

Martí-Carvajal AJ, Solà I. Treatment for anemia in people with AIDS. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD004776.

Notebaert E, Chauny JM, Albert M. Short-term benefits and risks of intravenous iron: a systematic review and meta-analysis. Transfusion. 2007 Oct;47(10):1905-18.

Reveiz L, Gyte GM, Cuervo LG. Treatments for iron-deficiency anaemia in pregnancy. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD003094.

Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology Clinical Practice Guideline Update. J Clin Oncol. 2007 Dec 21 [Epub ahead of print]

Review Date:
1/1/2008
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

A.D.A.M. Copyright

adam.com

Restless legs syndrome and related disorders

FitSugar — Wed, 08 Oct 2008 17:35:14 -0700

In This Report

Highlights
Introduction
Causes
Risk Factors
Complications
Diagnosis
Treatment
Medications
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Treatment

The American Academy of Sleep Medicine recommends medications for restless legs syndrome (RLS) or periodic limb movement disorder (PLMD) only for persons who fulfill strict diagnostic criteria and experience too much daytime sleepiness as a result of these conditions. (Excessive daytime sleepiness results from nighttime sleeplessness due to RLS or PLMD symptoms).
The U.S. Food and Drug Administration (FDA) announced in March 2007 that the dopamine agonist drug pergolide (Permax) has been voluntarily withdrawn from the market. This drug can cause serious damage to the heart valves of patients who take it.
The FDA approved pramipexole (Mirapex) for use in moderate-to-severe restless legs syndrome (RLS) in November 2006.
Bupropion (Wellbutrin), a newer antidepressant, may also be helpful for RLS. Bupropion, a weak dopamine reuptake inhibitor, causes a slight increase in the availability of dopamine in the brain. It is not addictive and does not have the severe side effects of other RLS drugs, but more research is needed to determine its usefulness. It is not FDA approved for RLS.

Research

Results from a large study show that RLS is more common in children and teens than epilepsy and diabetes. The study also found that more than 70% of affected children had at least one biological parent with RLS.
Two recently-published studies found an abnormal gene on chromosome 6 makes some people susceptible to RLS and PLMD.
People with type 2 diabetes have higher rates of secondary RLS. Nerve pain (neuropathy) related to their diabetes cannot fully explain this increased rate in RLS.

Introduction

Restless legs syndrome (RLS) is an unsettling and poorly understood movement disorder affecting 3 - 15% of the general population. RLS can affect both children and adults. Although effective treatments are available, the condition often remains undiagnosed.

Symptoms of RLS. The core symptom of RLS is an irresistible urge to move the legs (medically known as akathisia). Some people describe this symptom as a sense of unease and weariness in the lower leg, which is aggravated by rest and relieved by movement. Specific characteristics of RLS include:

"Pulling, searing, drawing, tingling, bubbling, or crawling" beneath the skin, usually in the calf area, causing an irresistible urge to move the legs. These sensations can occur not only in the lower legs, but they can also affect the thighs, feet, and even the upper body. RLS-type symptoms may also occur in the arms. This may be the first symptom of RLS in some people.
About 80% of patients with RLS also experience semi-rhythmic movements called periodic limb movement disorder (PLMD).
Itching and pain, particularly aching pain, may be present.
Patients experience symptoms when they feel most relaxed and their legs are at rest. (Movement, however, brings relief.) Symptoms usually occur at night when lying down, or sometimes during the day while sitting.
Episodes of RLS usually develop between 10 p.m. and 4 a.m. Symptoms are often most severe shortly after midnight. They typically occur for 30 - 60 seconds, and they usually resolve by morning. If the condition becomes more severe, people may begin to have symptoms during the day. These symptoms are always worse at night, however.
At night, the unpleasant sensations and the resulting uncontrollable urge to move the legs can often disturb sleep. Ignoring the need to move the legs usually only builds up tension until they jerk uncontrollably. If patients experience symptoms during the day, they usually feel compelled to move their legs in order to relieve the symptoms, making it difficult to sit during air or car travel or through classes or meetings.

Late-onset and Early-onset Forms. There appear to be two forms of RLS, early-onset and late-onset. Each form may have different characteristics:

People with early-onset RLS (occurring in the teenage years or earlier) tend to have a family history of the disorder. They also usually have RLS without accompanying pain.
Those with late-onset RLS usually do not have a family history of RLS. Their condition is more likely the result of a problem with the nervous system, and symptoms may include pain in the lower legs.

The medical term for periodic limb movement disorder (PLMD) is nocturnal myoclonus. PLMD symptoms include:

Episodes that usually occur during the night, peaking near midnight, as they do in restless legs syndrome (RLS).
Leg muscles contract and jerk every 20 - 40 seconds during sleep. Such movements may last less than 1 second, or as long as 10 seconds.
Unlike RLS, contractions in PLMD usually do not wake patients. PLMD is distinct from the brief and sudden movements that occur just as people are falling asleep, jolting them awake.

Although 80% of RLS sufferers have PLMD, only about 30% of people with PLMD also have RLS. While treatments for the two conditions are similar, PLMD is a separate syndrome. PLMD is also very common in narcolepsy, a sleep disorder that causes people to fall asleep suddenly and uncontrollably.

Cramps that awaken people during sleep are very common, and they are not part of restless legs syndrome or periodic limb movement disorder. They can be very painful and may cause a person jump out of bed in the middle of the night. They typically affect a specific area of the calf or the sole of the foot.

Circadian Rhythm. In sleep studies, subjects spend about one-third of their time asleep, suggesting that most people need about 8 hours of sleep each day. However, individual adults differ in the amount of sleep they need to feel well rested. Infants may sleep as many as 16 hours a day.

The daily cycle of life, which includes sleeping and waking, is called a circadian rhythm (circadian means "about a day"), or the biological clock. Hundreds of bodily functions follow biologic clocks, but sleeping and waking comprise the most prominent circadian rhythm. The sleeping and waking cycle is about 24 hours long. If confined to windowless apartments, with no clocks or other time cues, sleeping and waking only as their bodies dictate, humans typically live on slightly longer than 24-hour cycles.

The circadian rhythm usually takes the following daily patterns:

Humans prefer daytime activity and nighttime rest.
A natural peak in sleepiness occurs at mid-day, the traditional siesta time.
Daily rhythms interact with other factors that may interfere or change individual patterns:
- The fraction-of-a-second-firing of nerve cells in the brain may be faster or slower in different individuals.
- The monthly menstrual cycle in women can shift the pattern.

Light signals coming through the eyes reset the circadian cycles each day, so changes in season, or changes in exposures to light and dark, can unsettle the pattern.

The Response in the Brain to Light Signals. The brain's response to light signals is an important key factor in sleep:

Light signals travel to a tiny cluster of nerves in the hypothalamus (in the center of the brain). This cluster is the body's master clock, which is called the supra chiasmatic nucleus (SCN). The SCN is named for its location, which is just above (supra) the optic chiasm, a major junction where nerves transmit information about light from the eyes.
The approach of dusk each day prompts the SCN to signal the nearby pineal gland (named so because it resembles a pinecone) to produce the hormone melatonin.
Researchers think that melatonin acts as the body's time-setting hormone. It also appears to trigger the need to sleep. The longer a person is in darkness, the longer the duration of melatonin secretion. Staying in bright light can decrease the secretion of melatonin.

Sleep consists of two distinct states that alternate in cycles, and reflect differing levels of brain nerve cell activity:

Non-Rapid Eye Movement Sleep. Non-rapid eye movement (NREM) sleep is also called quiet sleep. NREM is further subdivided into three stages of progression:

Stage 1: Light sleep
Stage 2: "True" sleep
Stage 3 to 4: Deep "slow-wave" or delta sleep

With each ascending stage, awakening becomes more difficult. It is not clear what governs NREM sleep in the brain. A balance between certain hormones, particularly growth and stress hormones, may be important for deep sleep.

Rapid Eye-Movement Sleep. Rapid eye-movement (REM) sleep is also called active sleep. Most vivid dreams occur in REM sleep. Brain activity in REM sleep is comparable to that in waking, but the muscles are virtually paralyzed, possibly preventing people from acting out their dreams. Except for vital organs like the lungs and heart, the only muscles not paralyzed during REM sleep are the eye muscles. REM sleep may be critical for learning and for day-to-day mood regulation. When people are sleep-deprived, their brains must work harder than when they are well rested.

The REM/NREM Cycle. The cycle between quiet and active sleep generally follows this pattern:

After about 90 minutes of NREM sleep, eyes move rapidly behind closed lids, giving rise to REM sleep.
As sleep progresses the NREM/REM cycle repeats.
With each cycle, NREM sleep becomes progressively lighter, and REM sleep becomes progressively longer, lasting from a few minutes early in sleep to perhaps an hour at the end of the sleep cycle.

The hypothalamus is a highly complex structure in the brain that regulates many important brain chemicals. Malfunction of this area of the brain may give rise to cluster headaches.

Causes

The main cause of restless legs syndrome (RLS) is unknown. Researchers are investigating neurologic (nervous system) problems that may arise either in the spinal cord or the brain. One current theory suggests that a deficiency in a brain chemical called dopamine causes restless legs syndrome.

RLS may often have a genetic basis, particularly in those who develop it before age 40. When the condition occurs in older adults, it is most likely due to a neurological problem.

The central nervous system is comprised of the brain and spinal cord. The peripheral nervous system includes all peripheral nerves.

People with restless legs syndrome (RLS) often have a family history of the disorder. Researchers have detected specific genetic locations or factors that might be responsible for this condition. Much of the research comes from studies of families with a strong history of RLS-related conditions. In 2005, researchers linked a location on chromosome 12 to RLS. They named this genetic marker RLS1. Locations on chromosomes 14 and 9 may also be associated with hereditary forms of RLS.

Dopamine and Neurologic Abnormalities in the Brain. Some research suggests that neurologic abnormalities involved with restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) start in the brain. A variety of studies support the theory that an imbalance in neurotransmitters (chemical messengers in the brain), notably dopamine and serotonin, may play a part in RLS. Dopamine and serotonin cause numerous nerve impulses that affect muscle movement. The effect is similar to what happens in Parkinson's disease. Moreover, drugs that increase dopamine levels treat both disorders. However, Parkinson's disease itself does not seem to increase the risk for RLS. Nor does RLS early in life predispose to Parkinson's later on.

Neurologic Abnormalities in the Spine. Other research suggests that restless legs syndrome may be due to nerve impairment in the spinal cord. Researchers considered that such abnormalities were likely to start in nerve pathways in the lower spine. However, some patients with RLS have symptoms in the arms, indicating that the upper spine may also be involved.

Neuropathy. Some experts suggest that RLS, particularly if it occurs in older adults, may be a form of neuropathy, which is an abnormality in the nervous system outside the spine and brain. Nevertheless, there is no evidence of a causal relationship.

Iron deficiency, even at a level too mild to cause anemia, has been linked to restless legs syndrome (RLS) in some people. Studies suggest, in fact, that RLS in some people may be due to a problem with getting iron into cells that regulate dopamine in the brain. Some studies have reported RLS in 25 - 30% of people with low iron levels. The common connection between RLS and Parkinson's disease, in turn, may be not having enough iron in these patients.

The cause or causes of periodic limb movement disorder (PLMD) are not clear. Some research suggests that it may be due to abnormalities in the autonomic nervous system, which regulates the involuntary actions of the smooth muscles, heart, and glands.

Risk Factors

Restless legs syndrome (RLS) may affect 2.5 - 15% of the general population. It is more common in women than in men, and its frequency increases with age. The disorder affects an estimated 10 - 28% of adults older than age 65. In about 40% of patients, RLS begins in adolescence.

RLS may be more common than epilepsy and diabetes in children and teens. More than 70% of affected children in one study had at least one biological parent with RLS.

As many as two-thirds of people with restless legs syndrome (RLS) have a family history of the disorder. If so, RLS is more likely to occur before they turn 40. (A family history of RLS is less likely in people who develop it as older adults.) RLS is also more common in people from northern and western Europe, giving added support for a genetic basis for some cases.

Restless legs syndrome (RLS) and periodic leg movement disorder (PLMD) in children are strongly associated with inattention and hyperactivity. One study suggested that a quarter of children diagnosed with attention-deficit hyperactivity disorder (ADHD) also have RLS or PLMD, and this may actually contribute to inattentiveness and hyperactivity. The disorders have much in common, including poor sleep habits, twitching, and the need to get up suddenly and walk about frequently. Some evidence suggests that the link between the diseases may be a deficiency in the brain chemical dopamine.

About 20% of pregnant women report having restless legs syndrome (RLS). The condition usually goes away about a month after delivery. RLS in this population has been strongly associated with deficiencies in iron and the B vitamin folate.

Between 20 - 62% of people undergoing dialysis report restless legs syndrome. Symptoms often disappear after a kidney transplant.

Anxiety can cause restlessness and agitation at night. These symptoms can cause (or strongly resemble) restless legs syndrome.

The following medical conditions are also associated with restless legs syndrome (RLS), although the relationships are not clear. In some cases, these conditions may contribute to RLS, or they may have a common cause. In some cases, they may coexist due to other risk factors:

Osteoarthritis (degenerative joint disease). About 72% of patients with RLS also have osteoarthritis, a common type of arthritis affecting mostly older adults.
Varicose veins. Varicose veins occur in 14% of patients with RLS. Sclerotherapy treatments, in which doctors inject medications into affected veins, may relieve symptoms in such cases.
Obesity
Diabetes -- people with type 2 diabetes may have higher rates of secondary RLS. Nerve pain (neuropathy) related to their diabetes cannot fully explain this increased rate in RLS.
Hypertension
Hypothyroidism (a condition in which the thyroid gland does not make enough hormones)
Fibromyalgia (chronic pain of unknown cause)
Rheumatoid arthritis
Emphysema (a lung disease usually caused by smoking)
Chronic alcoholism
Sleep apnea (pauses in breathing during sleep) and snoring
Chronic headaches
Brain or spinal injuries

Many muscle and nerve disorders. Hereditary ataxia, a group of genetic diseases that affects the central nervous system and causes loss of motor control, is of particular interest. Researchers believe that hereditary ataxia may supply clues to the genetic causes of RLS.

Osteoarthritis is a chronic disease of the joint cartilage and bone, often thought to result from "wear and tear" on a joint, although there are other causes such as congenital defects, trauma, and metabolic disorders. Joints appear larger, are stiff and painful, and usually feel worse the more they are used throughout the day.

Click the icon to see an image of hypothyroidism.

Click the icon to see an image of fibromyalgia.

Click the icon to see an image of rheumatoid arthritis.

Click the icon to see an image of emphysema.

Several environmental and dietary factors can worsen or provoke restless legs syndrome (RLS):

Iron deficiencies. People who are deficient in iron are at risk for restless legs syndrome, even if they do not have anemia
Folic acid or magnesium deficiencies
Smoking
Alcohol abuse
Caffeine (coffee drinking is specifically associated with PLMD)
Stress
Fatigue
Prolonged exposure to cold

Drugs that worsen or provoke the condition include:

Antidepressants
Antipsychotic drugs
Anti-nausea drugs
Beta-blockers (a type of heart medication)
Antihistamines
Oral decongestants
Diuretics
Asthma drugs
Spinal anesthesia (anesthesia-induced restless legs syndrome typically disappears on its own within several months)

About 6% of the general population has periodic limb movement disorder (PLMD). Among the elderly, the prevalence increases to 25 - 58%. Studies suggest that PLMD may be especially common in elderly women. As with RLS, numerous conditions are associated with PLMD. They include sleep apnea, spinal cord injuries, stroke, narcolepsy, and diseases that destroy nerves or the brain over time. Certain medications, including some antidepressants and anti-seizure medications, may also contribute to PLMD.

Complications

Restless legs syndrome rarely results in any serious consequences. But in some cases, severe and persistent symptoms can cause considerable mental distress, chronic insomnia, and daytime sleepiness.

Sleep deprivation, and the daytime sleepiness that follows, is increasingly recognized as a cause of mood disruption and a contributor to industrial errors and motor vehicle crashes.

Effect on Daily Performance and Activities. Studies suggest that sleeplessness worsens many waking behaviors. These include:

Reduced concentration. Deep sleep deprivation appears to impair the brain's ability to process information.
Impaired task performance. Missing several hours of nightly sleep over the course of a week can negatively affect performance levels and mood. In fact, sleep deprivation can cause impaired performance levels comparable to those of intoxicated people.
Effect on learning. Whether sleeplessness significantly impairs learning is unclear. Some studies have reported problems in memorization, although others have found no differences in test scores between people with temporary sleep loss and those with full sleep.

In addition, since restless legs syndrome (RLS) is worse when resting, people with severe RLS may avoid daily activities that involve long periods of sitting, such as going to movies or traveling long distances.

Studies in Swedish working-aged men and women reported that those with restless legs syndrome (RLS) were more apt to be socially isolated, to have frequent daytime headaches or depression, and to complain of reduced libido or problems related to sleepiness.

RLS can contribute to insomnia. Insomnia itself can increase the activity of hormones and pathways in the brain that produce emotional problems. Even modest alterations in waking and sleeping patterns can have significant effects on a person's mood. Persistent insomnia may even predict the future development of mood disorders in some cases.

It is not clear if RLS is responsible for negative mood states or if anxiety or depression contributes to RLS. Anxiety can cause agitation and leg restlessness that resemble RLS, and depression and RLS symptoms also overlap. In addition, certain types of antidepressant drugs -- such as serotonin reuptake inhibitors -- can increase periodic limb movements during sleep.

Diagnosis

A diagnosis of restless legs syndrome or nocturnal leg cramps often relies solely on the patient's description of symptoms. In general, the recommended approach is first to take a sleep and personal history. The doctor may conduct an interview that includes the following questions:

How would you describe your sleep problem?
How long have you had this sleep problem?
How long does it take you to fall asleep?
How many times a week does the problem occur?
How restful is your sleep?
What are the leg problems like (cramps, twitching, crawling feelings)?
What is your sleep environment like? Noisy? Not dark enough?
What medications are you taking (including the use of antidepressants and self-medications -- such as herbs, alcohol, and over-the-counter or prescription drugs)?
Are you taking or withdrawing from stimulants, such as coffee or tobacco?
How much alcohol do you drink per day?
What stresses or emotional factors may be present in your life?
Have you experienced any significant life changes?
Do you snore or gasp during sleep? (This may be an indication of sleep apnea. Sleep apnea is a condition in which breathing stops for short periods many times during the night. It may worsen symptoms of restless legs syndrome or insomnia.)
If you have a bed partner, does he or she notice that you have jerking legs, interrupted breathing, or thrashing while you sleep?
Are you a shift worker?

Keeping a Record of Sleep. To help answer these questions, the patient may need to keep a sleep diary. Every day for 2 weeks, the patient should record all sleep-related information, including responses to questions listed above described on a daily basis. Recording sleep behavior using an extended-play audio or videotape can be very helpful in diagnosing sleep apnea.

A bed partner can help by adding their observations of the patient's sleep behavior.

Some high-risk patients may need to consult a sleep specialist or go to a sleep disorders center before their sleep problem can be diagnosed. At most centers, patients undergo an in-depth analysis, usually supervised by a team of consultants from various specialties, who can provide both physical and psychiatric evaluations. Centers should be accredited by the American Academy of Sleep Medicine.

Among the signs that may indicate a need for a sleep disorders center are:

Insomnia due to psychological disorders
Sleeping problems due to substance abuse
Snoring and sudden awakening with gasping for breath (possible sleep apnea)
Severe restless legs syndrome
Persistent daytime sleepiness
Sudden episodes of falling asleep during the day (possible narcolepsy)

Overnight polysomnography involves several tests to measure different functions during sleep. It is typically performed in a sleep center and may help rule out sleep apnea or confirm the effectiveness of restless legs syndrome (RLS) treatments.

The patient arrives about 2 hours before bedtime without having made any changes in daily habits. Polysomnography electronically monitors the patient as he or she passes, or fails to pass, through the various sleep stages. Polysomnography tracks the following:

Brain waves
Body movements
Breathing
Heart rate
Eye movements
Changes in breathing and blood levels of oxygen

Actigraphy uses a small wristwatch-like device (such as Actiwatch) to monitor sleep quality in people with suspected restless legs syndrome (RLS), periodic leg movement disorder (PLMD), insomnia, sleep apnea, and other sleep-related conditions. Patients can wear the device on their wrists or ankles. It measures and records muscle movements during sleep. For example, with PLMD, actigraphy can provide information on the total duration of movements, the number of occurrences, whether PLMD occurs simultaneously in both legs, and its effects on sleep.

Actigraphy is not as accurate as polygraphy because it cannot measure all the biological effects of sleep. It is more accurate than a sleep log, however, and very helpful for recording long periods of sleep.

The Epworth sleepiness scale uses a simple questionnaire to measure excessive sleepiness during eight situations.


Situation	Chance of Dosing
Sitting and reading	(Indicate a score of 0 to 3) 0 = no chance of dozing 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing
Watching TV	(Indicate a score of 0 to 3) 0 = no chance of dozing 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing
Sitting inactive in a public place	(Indicate a score of 0 to 3) 0 = no chance of dozing 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing
Riding as a passenger in a car for an hour without a break	(Indicate a score of 0 to 3) 0 = no chance of dozing 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing
Lying down to rest in the afternoon when circumstances permit	(Indicate a score of 0 to 3) 0 = no chance of dozing 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing
Sitting and talking to someone	(Indicate a score of 0 to 3) 0 = no chance of dozing 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing
Sitting quietly after a lunch without alcohol	(Indicate a score of 0 to 3) 0 = no chance of dozing 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing
Sitting in a car while stopped for a few minutes in traffic	(Indicate a score of 0 to 3) 0 = no chance of dozing 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing
Score Results 1-6: Getting enough sleep. 4-8: Tends to be sleepy but is average. 9 and over: Very sleepy and suggestive of sleep-disordered breathing. Patient should seek medical advice.

Because of the high association between restless legs syndrome and iron deficiency, a test for low iron stores should be part of the diagnostic workup in restless legs syndrome (RLS). There are two steps in making this diagnosis:

The first step is to determine if a person is actually deficient in iron.
If iron stores are low, 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 (hypochromic) and abnormally small (microcytic). They are also mostly uneven in shape. These findings suggest iron deficiency, but they can also appear in anemia resulting from chronic disease and in thalassemia.
Hemoglobin and iron levels are low. These findings further suggest iron deficiency, but they can also occur in cases of anemia due to chronic disease.
Ferritin levels are low. Ferritin is a protein that binds to iron, and low levels typically mean the patient does not have enough iron in their body. However, high levels of ferritin in the blood do not always mean a patient has enough iron. For example, pregnant women may have high ferritin levels even in their third trimester, yet still be iron deficient. Ferritin levels may also be normal, or even elevated, in patients with inflammation resulting from anemia due to chronic disease, even if these patients also so not have enough iron in their body.
A test that measures a factor called serum transferrin receptor (TfR) is proving to be very sensitive in identifying iron deficiency in some patients, including the elderly with chronic diseases and possibly pregnant women.

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 is rare in adults.
Heavy menstrual or abnormal uterine bleeding is usually the cause of iron deficiencies in young women. Increased need for iron during pregnancy is also a common cause of iron deficiency in pregnant women.
If doctors suspect internal bleeding as the cause of iron deficiency, they look first to the digestive tract as the possible source. A diagnosis in such cases can often be made if the patient has noticed blood in their stools, (the stool would be black and tarry or red-streaked). Often, however, bleeding may be present but not visible. In such cases, stool tests for this hidden (occult) blood are required. The patient may need additional tests to diagnose the cause of bleeding. One common test is endoscopy, in which a fiberoptic tube is used to look into the gastrointestinal tract. Doctors recommend it particularly when the source of bleeding is unclear.

If the patient's diet suggests low iron intake and doctors cannot find other causes of iron deficiency, they may recommend a month-long trial of iron supplements. If the patient fails to respond, they will need further evaluation.

Certain laboratory tests may be helpful in determining causes of restless legs syndrome (RLS) or conditions that rule it out. They include:

Blood glucose tests for diabetes
Tests for kidney problems
In certain cases, tests for thyroid hormone, magnesium, and folate levels

In addition to other sleep-related leg disorders, a number of other medical conditions may have features that resemble restless legs syndrome (RLS). The doctor will need to consider these disorders in making a diagnosis.

Peripheral Neuropathies. Peripheral neuropathies are nerve disorders in the hands or feet. Several conditions can cause these disorders, and they can produce pain, burning, tingling, or shooting sensations in the arms and legs. Diabetes is a very common cause of painful peripheral neuropathies. Other causes include alcoholism, rheumatoid arthritis, systemic lupus erythematosus, amyloidosis, HIV infection, kidney failure, and certain vitamin deficiencies. Symptoms of peripheral neuropathies may mimic RLS. However, unlike RLS, they are not usually associated with restlessness, movement does not relieve the discomfort, and they do not worsen at bedtime.

Deep Vein Thrombosis. Deep vein thrombosis (DVT) is a blood clot in a deep vein in the body, usually in the leg. It may cause pain, swelling, and aching in the leg where the clot has developed. It can occur in people with heart disease, with varicose veins, during pregnancy, in women from hormonal treatments, from injury to the leg, or from inactivity (such as after surgery or during long flights). In women, it can also result from hormonal treatments. Left untreated, DVT can be a very serious and even life-threatening condition.

This picture shows a red and swollen thigh and leg caused by a blood clot (thrombus) in the deep veins in the groin (iliofemoral veins), which prevents normal return of blood from the leg to the heart.

Intermittent Claudication and Peripheral Artery Disease. Peripheral artery disease (PAD) occurs when atherosclerosis (commonly called hardening of the arteries) affects the feet and legs. In such cases, blocked arteries reduce the flow of oxygen-rich blood to the legs or feet. Intermittent claudication is an important symptom of PAD and occurs in between one-third and one-half of these patients. The word claudication describes the pain that occurs in PAD patients when they exercise, particularly when they walk. In intermittent claudication, blood flows only enough to meet the needs of the person at rest. The result is leg pain during exercise, which disappears during rest.

Click the icon to see an image of peripheral artery disease.

Akathisia. Akathisia is a state of restlessness or agitation, and feelings of muscle quivering. A condition called hypotensive akathisia is caused by failure in the autonomic nervous system. Unlike RLS, it occurs at any time of the day and usually only when the patient is sitting -- not lying down. Drugs used to treat schizophrenia and other psychoses can cause akathisia, as can anti-nausea drugs. The condition also occurs when drugs to treat Parkinson's disease are withdrawn.

Painful Legs and Moving Toes Syndrome. A rare disorder affecting one or both legs, painful legs and moving toes syndrome is marked by a constant, deep, throbbing ache in the limbs and involuntary toe movements. The discomfort may be mild or severe. It gets worse with activity and usually stops during sleep. Usually, the cause is unknown, though it may arise from spinal injuries or herpes zoster infection. The condition is difficult to treat, although the drug baclofen, combined with either clonazepam or carbamazepine, has shown some success. Other treatments that may help include orthotics for the shoes and transcutaneous electrical nerve stimulation (TENS).

Meralgia Paresthetica. An uncommon nerve condition, meralgia paresthetica causes numbness, pain, tingling, or burning on the front and side of the thigh. It usually occurs on one side of the body, and the cause may be compression of the thigh nerve as it passes through the pelvis. It typically occurs in people aged 30 - 60 years, but it can affect people of all ages. It often goes away on its own.

Treatment

The first step in treating a patient who complains of sleeplessness and restless legs syndrome is to try to improve sleep and eliminate possible causes of restless legs syndrome (RLS). Doctors normally try to achieve these goals without the use of drugs, initially. A non-drug approach is a particularly important first step for elderly patients.

The doctor should first try to treat any underlying medical conditions that may be causing restless legs.
If medications may be causing RLS, the doctor should try to prescribe alternatives, if possible.

If the cause cannot be determined, it is best to first try better sleep habits and relaxation methods. These approaches may help, even if the patient needs drug therapy later on.

Some people report help or relief from restless legs syndrome (RLS) with the following behaviors or devices:

Hot baths or cold compresses help some patients.
Ergonomic measures -- for example, patients might find it useful to work at a high stool, where they can dangle their legs. In meetings or during air travel, it is helpful to have an aisle seat.
Changing sleep patterns -- some patients report that symptoms do not occur if they sleep late in the morning. Therefore, if feasible, patients can try changing sleep patterns.
Avoiding caffeine, alcohol, and nicotine also improves some cases of RLS.

Some patients recommend alternative treatments for RLS, such as acupuncture and massage. To date, however, there is not enough data on the effectiveness of these treatments.

Some people have reported benefits from:

Vitamin E (800 - 1,200 IU per day)
Calcium, magnesium, or potassium supplements
Folic acid supplements for people with folate deficiencies

Folate (folic acid) is necessary for the production of red blood cells and for the synthesis of DNA (which controls heredity and is used to guide the cell in its daily activities). Folic acid also helps with tissue growth and cell function. In addition, it helps to increase appetite when needed and stimulates the formation of digestive acids.

Because restless legs syndrome (RLS) is associated with iron insufficiency, people with the condition should get enough iron from their diet. [See In-Depth Report #57: Anemia.] Iron is found in foods either in the form of heme or non-heme iron:

Foods containing heme iron are the best for increasing or maintaining healthy iron levels. Such foods include (in decreasing order of iron-richness) clams, oysters, organ meats, beef, pork, poultry, and fish.
Non-heme iron is less well absorbed. About 60% of the iron in meat is non-heme (although meat itself helps absorb non-heme iron). Eggs, dairy products, and iron-containing vegetables (including dried beans and peas) have only the non-heme form. Other sources of non-heme iron include iron-fortified cereals, bread, and pasta products, dark green leafy vegetables (chard, spinach, mustard greens, kale), dried fruits, nuts, and seeds.

The Effects of Food on Iron Absorption. The absorption of non-heme iron often depends on the food balances in meals. The following are foods that enhance absorption of non-heme iron.

Meat and fish not only contain heme iron, the best form for maintaining stores, but they also help absorb non-heme iron.
Eating more vitamin C-rich foods can enhance absorption of non-heme iron during a single meal. In any case, vitamin C-rich foods are healthy. They include broccoli, cabbage, citrus fruits, melon, tomatoes, and strawberries. One orange or 6 ounces of orange juice can double the amount of iron your body absorbs from plant foods. (Taking vitamin C supplements does not appear to have any significant effect on how much iron your body stores.)
Foods containing riboflavin (vitamin B2) may help enhance the formation of hemoglobin from iron. Sources include liver, dried fortified cereals, and yogurt.

Certain nutrients impede the body's absorption of dietary iron. They include:

Polyphenols (found in tea, coffee, red wine, berries, and apples)
Phytates (found in foods such as seeds, dried beans, soy, and bran). Such foods are typically high in fiber. It is often believed that fiber itself impedes iron absorption, but researchers report that it has little or no effect.
Calcium. Calcium impairs the absorption of heme and non-heme iron. However, calcium intake must be quite high to cause any significant problems.

The Effects of Cooking Methods on Iron. Cooking methods can enhance the amount of iron in your body. Cooking in cast iron pans and skillets is a well-known way to increase the iron content of food. According to one study, boiling, steaming, or stir-frying in utensils composed of any material significantly increased the release of non-heme iron stored in vegetables.

Iron supplements can significantly reduce symptoms in people with restless legs syndrome (RLS) who are also iron deficient. Patients should use them only when dietary measures have failed. Iron supplements do not appear to be useful for RLS patients with normal or above normal iron levels.

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. A reasonable approach for patients with RLS is to take 65 mg of iron (or 325 mg of ferrous sulfate) along with 100 mg of vitamin C on an empty stomach, 3 times a day.

IMPORTANT: As few as 3 adult iron tablets can poison, and even kill, children. This includes any form of iron pill. No one, not even adults, should take a double dose of iron if they miss one dose.

Tips for taking iron are:

For best absorption, take iron between meals. (Iron may cause stomach and intestinal disturbances, however. Some experts believe that you can take low doses of ferrous sulfate with food and avoid the side effects.)
Always drink a full 8 ounces of fluid with an iron pill.
Keep tablets in a cool place. Bathroom medicine cabinets may be too warm and humid, which may cause the pills to disintegrate.

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

Constipation and diarrhea -- these are rarely severe, although iron tablets can aggravate existing digestive problems such as ulcers and ulcerative colitis.
Nausea and vomiting may occur with high doses, but you can control this by taking smaller amounts. Switching to ferrous gluconate may help some people with severe digestive 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 occurs, bleeding in the digestive tract may be causing the iron deficiency, and the patient should call the doctor immediately.
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:

Antibiotics: tetracycline, penicillamine, and ciprofloxacin
Anti-Parkinson's disease drugs: methyldopa, levodopa, and carbidopa

At least 2 hours should elapse between doses of these drugs and doses of iron supplements.

Supplementary Treatments. The following supplements may improve iron absorption:

Adding either ascorbic acid (vitamin C) or succinic acid to ferrous sulfate treatment will improve absorption of iron stores. Ascorbic acid added to iron treatment, however, may worsen 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 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.

Exercise earlier in the day may be one of the best ways to achieve healthy sleep. However, vigorous exercise and stimulation (including sexual activity) within 1 - 2 hours of bed time may worsen restless legs syndrome (RLS). A study found that people who walked briskly for 30 minutes, four times a week, improved minor sleep disturbances after 4 months. Regular, moderate exercise, healthful in any case, may help prevent RLS. Patients report that either bursts of excessive energy or long sedentary periods worsen symptoms.

Benign nocturnal leg cramps, sometimes known as a charley horse, are muscle spasms in the calf that can occur one or many times during the night. Cramping may also occur in the soles of the feet. They typically last from a few seconds to a few minutes. Some people experience them regularly, others only on isolated occurrences.

Causes of Nocturnal Leg Cramps. In most cases, the cause of nocturnal leg cramps remains unknown. Among the conditions that might cause leg cramps are:

Calcium and phosphorus imbalances, particularly during pregnancy
Low potassium or sodium (salt) levels
Overexertion, standing on concrete for long periods, or prolonged sitting (especially with the legs contorted)
Having structural disorders in the legs or feet (such as flat feet)
Medical causes of muscle cramping include hypothyroidism, Addison's disease, uremia, hypoglycemia, anemia, and certain medications. Various diseases that affect nerves and muscles, such as Parkinson's, cause leg cramps. Peripheral neuropathy, a complication of diabetes, can cause cramp-like pain, numbness, or tingling in the legs. Patients with kidney disease undergoing dialysis are also prone to leg cramps.

Individuals at Higher Risk for Nocturnal Leg Cramps. Nocturnal leg cramps occur at all ages but peak at different times. They are particularly common in adolescence, during pregnancy, and in older age, affecting up to 70% of adults over age 50 at some point.

Pregnant women and those taking diuretics are also at risk for leg cramps because of low calcium levels and an imbalance in calcium and phosphorus.

Consequences of Nocturnal Leg Cramps. Nocturnal leg cramps, like restless legs syndrome, rarely have any serious consequences. However, they can be extremely painful and long lasting. In some cases, severe and persistent symptoms can cause chronic insomnia and considerable mental distress.

Managing Nocturnal Leg Cramps. Once a cramp begins, straighten the leg, flex the foot upward toward the knee, or grab the toes and pull them toward the knee.

Walking or shaking the affected leg, then elevating it, may also help.

If soreness persists, a warm bath or shower or an ice pack may bring relief.

Lifestyle Tips for Preventing Nocturnal Leg Cramps. Nighttime leg cramps are generally treated with lifestyle changes.

Everyone with leg cramps should drink plenty of water (at least 6 - 8 glasses daily) to maintain adequate fluid levels.
Pregnant women and others who get legs cramps due to low calcium levels should reduce milk intake, because drinking milk does not correct the underlying imbalances in calcium and phosphorus. Instead, they should boost calcium levels by taking nonphosphate calcium supplements.
To prevent cramps from occurring, nightly stretching exercises may be the best preventive measure. Patients should stand about 30 inches from a wall and, keeping the heels flat on the floor, lean forward and slowly move the hands up the wall to achieve a comfortable stretch. A few minutes on a stationary bicycle at bedtime may also help.
While in bed, loose covers should be used to prevent the toes and feet from pointing, which causes calf muscles to contract and cramp. Propping the feet up higher than the torso may also help.
During the week, swimming and water exercises are a good way to keep muscles stretched, and wearing supportive footwear is also important.

Quinine. Quinine had been widely used to prevent leg cramping. The U.S. Food and Drug Administration (FDA) banned its sale over the counter because it reportedly caused some serious, although rare, side effects. These side effects include bleeding problems and heart irregularities. Other, less serious side effects include headaches, vision problems, and rash.

The FDA has since banned the marketing of most quinine drugs, cautioning against the off-label (non-approved) use of the drug to treat RLS. Only one form of the drug, Qualaquin, is approved for sale, for the treatment of some types of malaria. Pregnant women and those with liver problems should avoid quinine in any form.

Supplements. Some small studies indicate that the mineral magnesium, taken as magnesium citrate or magnesium lactate, may provide some benefit to people with leg cramps, including pregnant women.

In one small study, taking vitamin B complex was helpful. Other supplements tried for leg cramps include vitamin E, calcium, and potassium or sodium chloride, but these do not appear to be very effective. Sodium chloride (salt) may be helpful, but Western diets already contain too much sodium.

Medications

The American Academy of Sleep Medicine recommends medications for restless legs syndrome (RLS) or periodic limb movement disorder (PLMD) only for persons who fit strict diagnostic criteria, and who experience excessive daytime sleepiness as a result of these conditions. (Excessive daytime sleepiness results from nighttime sleeplessness due to RLS or PLMD symptoms). Little is known about the best way to treat RLS, but some experts suggest the following:

Over-the-counter pain relievers and possibly mineral and vitamin supplements (particularly folic acid in people who might be deficient) should be the first form of treatment.
People with RLS should have a test for iron deficiency. If they are iron deficient, they should start treatment with iron supplements.
Dopaminergic drugs (drugs that increase levels of dopamine) are the standard medicines for treating severe RLS, PLMD, or both.
Other drugs may be helpful if dopaminergic drugs fail, or for patients who have frequent -- but not nightly -- symptoms. These include opiates (pain relievers), benzodiazepines (sedative hypnotic drugs), or anticonvulsants. However, benzodiazepines and opiates can become habit forming and addictive.

Before taking stronger medications, people should try over-the-counter pain relievers, such as acetaminophen (Tylenol) or non-steroidal anti-inflammatory drugs (NSAIDs), which include ibuprofen (Advil, Motrin, Rufen), naproxen (Anaprox, Naprosyn, Aleve), and ketoprofen (Orudis KT, Aktron).

Although NSAIDs work well, long-term use can cause stomach problems, such as ulcers and bleeding, and possible heart problems. In April 2005, the Food and Drug Administration asked drug manufacturers of NSAIDs to include a warning label on their product that alerts users of an increased risk for heart-related problems and digestive tract bleeding.

Dopaminergic drugs increase the availability of the chemical messenger dopamine in the brain, and are the first-line treatment for severe restless legs syndrome (RLS) and periodic leg movement disorder (PLMD). These drugs significantly reduce the number of limb movements per hour, and improve the subjective quality of sleep. Patients with either condition who take these drugs have experienced up to 100% reduction in symptoms.

Dopaminergic drugs, however, can have severe side effects (they are ordinarily used for Parkinson's disease). They do not appear to be as helpful for RLS related to dialysis as they do for RLS from other causes.

Dopaminergic drugs include dopamine precursors and dopamine receptor agonists.

Dopamine Precursors. The dopamine precursor levodopa (L-dopa) was once a popular drug for severe RLS. The standard preparations (Sinemet, Atamet) combine levodopa with carbidopa, which improves the action of levodopa and reduces some of its side effects, particularly nausea. Levodopa can also be combined with benserazide (Madopar) with similar results, but Sinemet is almost always used in America. (Levodopa combinations are well tolerated and safe.)

Patients typically start with a very low dose taken 1 hour before bedtime. The dosage is increased until the patient finds relief. Patients sometimes need to take an extended form or to take it again during the night.

Levodopa acts fast, and the treatment is usually effective within the first few days of therapy. One study reported that a combination therapy of regular-release L-dopa plus sustained release L-dopa was effective in improving sleep.

Serious common side effects of L-dopa treatment (and, to lesser extent, of dopamine receptor agonists) are augmentation and rebound. Many studies report that augmentation (worsening of symptoms that occur earlier in the day) occurs in up to 70% of patients who take L-dopa. The risk is highest for patients who take daily doses, especially doses at high levels (greater than 200 mg/day). For this reason, patients should use L-dopa only intermittently (fewer than 3 times per week). The drug should be immediately discontinued if augmentation does occur. Following withdrawal from L-dopa, patients can switch to a dopamine receptor agonist.

The rebound effect causes increased leg movements at night or in the morning as the dose wears off, or as tolerance to the drug builds up.

Dopamine Receptor Agonists. Dopamine receptor agonists (also called dopamine agonists) mimic the effects of dopamine by acting on dopamine receptors in the brain. They are now generally preferred to L-dopa. Because they have fewer side effects than L-dopa, including rebound effect and augmentation, these drugs may be used on a daily basis. (Rebound effect is the worsening of symptoms over time; augmentation means the appearance of symptoms earlier in the day. About 30% of patients who take dopamine receptor agonists have reported augmentations symptoms. As the newer drugs are taken for longer periods and at higher doses, however, their augmentation rates may become closer to those of L-dopa.)

Dopamine agonists have been shown to relieve symptoms in 70 - 90% of patients. Dopamine agonists can be ergot-derived (such as cabergoline) or non-ergot derived (such as pramipexole and ropinirole). The newer non-ergotamine derivatives may induce fewer side effects than ergot-derived drugs. Studies on these medications report the following:

Ropinirole (Requip) is a non-ergotamine dopamine agonist. Approved in 2005, ropinirole is the first drug approved specifically for treatment of moderate-to-severe RLS (more than 15 RLS episodes a month). Side effects are generally mild but may include nausea, vomiting, drowsiness, and dizziness.
The Food and Drug Administration (FDA) approved pramipexole (Mirapex) for use in moderate-to-severe RLS in November 2006. However, patients may fall asleep, without warning, while taking this drug, even while performing activities such as driving.

Cabergoline (Dostinex) is also showing promise in clinical trials. In one study, cabergoline was used for RLS after levodopa had either failed or resulted in increased symptoms. Patients in the study reported relief or freedom from symptoms after 4 weeks of use. A 2006 study indicated that a single evening dose of cabergoline improved both day and nighttime limb movements, and sleep disturbances.The FDA announced in March 2007 that the dopamine agonist pergolide (Permax) was voluntarily withdrawn from the market. Studies confirmed that this drug could cause serious damage to the heart valves of patients who take it. These problems have not been reported with ropinirole or pramipexole, which are chemically different then pergolide.

Other Dopamine Agonists. Rotigotine is a unique dopamine agonist that is being developed in patch form for RLS. In May 2007, the FDA approved this patch for treatment of early Parkinson's disease. Other dopamine agonists that have shown some promise in small studies include alpha-dihydroergocryptine, or DHEC (Almirid), and piribedil (Trivastal).

Regimens. The effects of L-dopa are apparent in 15 - 30 minutes. Dopamine receptor agonists, meanwhile, take at least 2 hours to start working. Some doctors recommend regular use of dopamine receptor agonists for patients who experience nightly symptoms, and L-dopa for those whose symptoms occur only occasionally.

Side Effects. Common side effects of dopaminergic drugs vary but may include feeling faint or dizzy (especially when standing up), headaches, abnormal muscle movements, rapid heartbeat, insomnia, bloating, chest pain, and dry mouth. Nausea may be especially common. Adding the drug domperidone may help to relieve this side effect. In rare cases, dopaminergic drugs can cause hallucinations or lung disease.

Because these drugs may cause daytime drowsiness, patients should be extremely careful while driving or performing tasks that require concentration.

Long-term use of dopaminergic drugs can lead to loss of effectiveness (tolerance). Adding a drug called entacapone (Comtan) may prolong the duration of action of carbidopa-levodopa therapy (Sinemet), but it can cause nausea.

Rebound effect, augmentation, and tolerance can reduce the value of dopaminergic drugs in the treatment of RLS. Using the lowest dose possible can minimize these effects.

Withdrawal Symptoms. Patients who withdraw from these drugs typically experience very severe RLS symptoms for the first 2 days after stopping. RLS eventually returns to pre-treatment levels after about a week. The longer a patient uses these drugs, the worse their withdrawal symptoms.

Benzodiazepines, such as clonazepam (Klonopin), are known as sedative hypnotics. Doctors prescribe them for insomnia and anxiety. They may be helpful for some patients with restless legs syndrome (RLS) that disrupts sleep. Clonazepam may be particularly helpful for children with both periodic limb movement disorder and symptoms of attention deficit hyperactivity disorder. The medicine also may be helpful for patients with RLS who are undergoing dialysis.

Side Effects. Elderly people are more susceptible to side effects. They should usually start at half the dose prescribed for younger people, and should not take long-acting forms. Side effects may differ depending on whether the benzodiazepine is long-acting or short-acting.

The drugs may increase depression, a common condition in many people with insomnia.
Breathing problems may occur with overuse or in people with pre-existing respiratory illness.
Long-acting drugs have a very high rate of residual daytime drowsiness compared to others. They have been associated with a significantly increased risk for automobile accidents and falls in the elderly, particularly in the first week after taking them. Shorter-acting benzodiazepines do not appear to pose as high a risk.
There are reports of memory loss (so-called traveler's amnesia), sleepwalking, and odd mood states after taking triazolam (Halcion) and other short-acting benzodiazepines. These effects are rare and probably enhanced by alcohol.
Because benzodiazepines cross the placenta and enter breast milk, pregnant and nursing women should not use them. There are some reports of an association between the use of benzodiazepines in the first trimester of pregnancy and the development of cleft lip in newborns. Studies are conflicting at this point, but, due to other known side effects of benzodiazepines, pregnant women should not use these drugs, if possible.
In rare cases, overdoses have been fatal.

Interactions. Benzodiazepines are potentially dangerous when used in combination with alcohol. Some drugs, such as the ulcer medication cimetidine, can slow the breakdown of benzodiazepine.

Withdrawal Symptoms. Withdrawal symptoms usually occur after prolonged use and indicate dependence. They can last 1 - 3 weeks after stopping the drug and may include:

Gastrointestinal distress
Sweating
Disturbed heart rhythm
In severe cases, patients might hallucinate or experience seizures, even a week or more after they stop taking the drug.

Rebound Insomnia. Rebound insomnia, which often occurs after withdrawal, typically includes 1 - 2 nights of sleep disturbance, daytime sleepiness, and anxiety. The chances of rebound are higher with the short-acting benzodiazepines than with the longer-acting ones.

Narcotics are pain-relieving drugs that act on the central nervous system. They are sometimes prescribed for severe cases of restless legs syndrome (RLS). They may be a good choice if pain is a prominent feature. Some evidence also suggests that narcotics reduce the frequency of periodic leg movements.

There are two types of narcotics, both of which have been used for severe RLS:

Opiates (such as morphine and codeine) come from natural opium. Some patients report relief with the use of the opiate fentanyl (Duragesic), available in skin patch form. An implanted pump that uses morphine and an anesthetic called bupivacaine is showing promise for patients with severe RLS. The pump delivers the drugs to the fluid surrounding the spinal cord (cerebrospinal fluid).
Opioids are synthetic drugs. The most common example is oxycodone (Percodan, Percocet, Roxicodone, Oxycontin). Apomorphine is a morphine derivative. In one study, when injected under the skin at night, it reduced nocturnal discomfort and leg movements in some patients.

Although the use of narcotics for severe RLS is controversial, some studies have suggested that even when the treatments are long-term, they are rarely addictive for pain sufferers except among patients with a history of substance abuse.

The use of such drugs may be beneficial when included as part of a comprehensive pain management program. Such a program involves screening prospective patients for possible drug abuse, and regularly monitoring those who are taking narcotics. Doses should be adjusted as necessary to achieve an acceptable balance between pain relief and side effects. Patients on long-term opiate therapy should also be monitored periodically for sleep apnea, a condition that causes breathing to stop for short periods many times during the night. Sleep apnea may worsen symptoms of RLS, insomnia, and other complaints.

Tramadol. Tramadol (Ultram) is a pain reliever that has been used as an alternative to opioids. In one study, tramadol was very effective for RLS and produced few or no side effects. It has opioid-like properties, but is not as addictive. (However, there are reports of dependence and abuse with this drug as well.) Withdrawal after long-term use (longer than a year) can cause intense symptoms, including diarrhea, insomnia, and even restless legs syndrome itself.

Antiseizure drugs -- such as gabapentin (Neurontin), valproic acid (valproate, divalproex, Depakote, Depakene), and carbamazepine (Tegretol) -- relax blood vessels and are being tested for restless legs syndrome (RLS). Gabapentin, a newer antiseizure drug, is showing particular promise for mild-to-moderate RLS. One study reported that it improved RLS symptoms and sleep, particularly in patients who also experienced pain. It was also effective for periodic leg movement disorder. A new gabapentin product is in phase III clinical trials for the treatment of RLS. The new drug, known as XP13512, converts to gabapentin in the intestines, and therefore may reduce some of the side effects experienced by patients taking antiseizure medications.

Side Effects. All antiseizure drugs have potentially severe side effects. Therefore, patients should try these medications only after non-drug methods have failed. Side effects of many anti-seizure drugs include nausea, vomiting, heartburn, increased appetite with weight gain, hand tremors, irritability, and temporary hair thinning and hair loss (taking zinc and selenium supplements may help reduce this last effect). Some antiseizure drugs can also cause birth defects and, in rare cases, liver toxicity. Gabapentin may have fewer of these side effects than valproic acid or carbamazepine.

Antidepressants. Bupropion (Wellbutrin), a newer antidepressant, may be helpful for restless legs syndrome (RLS). Bupropion is a weak dopamine reuptake inhibitor -- it causes a slight increase in the availability of dopamine in the brain. The drug is not addictive and does not have the severe side effects of other RLS drugs, but more research is needed to determine if it is useful.

Clonidine. Clonidine (Catapres), a drug used for high blood pressure, is helpful for some patients and may be an appropriate choice for patients who have RLS accompanied by hypertension. It also may help patients with RLS who are undergoing hemodialysis.

Baclofen. The anti-spasm drug baclofen (Lioresal) appears to reduce intensity of RLS (although not frequency of movements).

Resources

www.aasmnet.org -- American Academy of Sleep Medicine
www.sleepfoundation.org -- National Sleep Foundation
www.ninds.nih.gov -- National Institute of Neurological Disorders and Stroke
www.nhlbi.nih.gov/about/ncsdr/ -- National Center on Sleep Disorders Research
www.rls.org -- Restless Legs Syndrome Foundation
www.wemove.org -- Worldwide Education and Awareness for Movement Disorders

References

Bogan RK, Fry JM, Schmidt MH, Carson SW, Ritchie SY. Ropinirole in the treatment of patients with restless legs syndrome: a US-based randomized, double-blind, placebo-controlled clinical trial. Mayo Clin Proc. 2006 Jan;81(1):17-27.

Claman DM; Redline S; Blackwell T, Ancoli-Israel S, Surovec S, Scott N, et al. Prevalence and correlates of periodic limb movements in older women. J Clin Sleep Med. 2006 Oct;2(4):438-445.

Merlino G, Fratticci L, Valente M, et al. Association of restless legs syndrome in type 2 diabetes: a case-control study. Sleep. 2007; 30(7): 866-71.

Oertel WH, Benes H, Bodenschatz R, Peglau I, Warmuth R, Happe S, et al. Efficacy of cabergoline in restless legs syndrome: a placebo-controlled study with polysomnography (CATOR). Neurology. 2006 Sep 26;67(6):1040-6.

Partinen M, Hirvonen K, Jama L, Alakuijala A, Hublin C, Tamminen I, et al. Efficacy and safety of pramipexole in idiopathic restless legs syndrome: a polysomnographic dose-finding study--the PRELUDE study. Sleep Med. 2006 Aug;7(5):407-17.

Picchietti D, Winkelman JW. Restless legs syndrome, periodic limb movements in sleep, and depression. Sleep. 2005 Jul 1;28(7):891-8.

Picchietti D. Restless legs syndrome: prevalence and impact in children and adolescents--the Peds REST study. Pediatrics. 2007; 120(2): 253-66.

Stefansson H, Rye DB, Hicks A, et al. A Genetic Risk Factor for Periodic Limb Movements in Sleep. N Engl J Med. 2007;357:639-47.

Winkelman JW, Sethi KD, Kushida CA, Becker PM, Koester J, Cappola JJ, et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurology. 2006 Sep 26;67(6):1034-9.

Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet (in press). [cited in: Winkelmann J. Periodic Limb Movements in Sleep - Endophenotype for Restless Legs Syndrome? N Engl J Med. 2007; 357:703-05.]

Review Date:
10/22/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Iron

FitSugar — Wed, 08 Oct 2008 17:35:25 -0700

Overview

Overview
Uses
Dietary Sources
Available Forms
How to Take It
Precautions
Possible Interactions
Supporting Research

HEALTH GUIDE REFERENCE FROM A.D.A.M

Overview

Iron is an essential mineral that contributes to many important physiologic functions in the body. Much of the iron in the body is attached to hemoglobin molecules in red blood cells, thereby delivering oxygen to all of the tissues. Extra iron is stored in the liver, bone marrow, spleen, and muscles.

Significant deficiency in iron leads to anemia. The most common symptoms of anemia are weakness and fatigue. Pregnant women, young women during their reproductive years, and children tend to be at the highest risk of becoming deficient in iron. Anemia may be mild, moderate, or severe and may be caused by significant or prolonged blood loss such as that from a bleeding ulcer, menstruation, severe trauma, surgery, or a malignant tumor. It can also be caused by an iron-poor diet, inefficient absorption of dietary iron, pregnancy, and the rapid growth that takes place during infancy, early childhood, and adolescence.

On the other hand, excessive iron in the body can lead to a condition known as hemochromatosis, which can cause diabetes, liver damage, and discoloration of the skin.

The World Health Organization (WHO) considers iron deficiency the number one nutritional disorder in the world. As many as 80% of the world's population may be iron deficient, while 30% may have iron deficiency anemia.

Uses

Anemia

The most important use of iron supplements is to treat anemia caused by iron deficiency. Anemia is low levels of iron in the blood. Iron is important, as it is a key component of hemoglobin, which carries oxygen to our tissues. Anemia can be caused by many conditions, including PMS and menopausal loss, pregnancy, blood donation, bleeding ulcers, surgery (before and after), and chronic diseases such as cancer and kidney failure. Anemia treatment is directed and supervised by a health care provider, who may first search for the underlying reason for the low levels of iron.

Exercise capacity

Low levels of iron can lead to diminished exercise capacity, whether anemia is present or not. Therefore, if your iron stores are low (as measured by your doctor), iron supplements (for example, in a multivitamin or iron supplement) may improve endurance during aerobic activities.

Attention-deficit hyperactivity disorder (ADHD)

Symptoms of iron deficiency (including decreased attention, arousal, and social responsiveness) are similar to symptoms of attention-deficit hyperactivity disorder (ADHD). There is little clinical evidence, however, that iron supplementation improves behavior in children with ADHD who are deficient in iron. Since iron can be toxic in children who are not deficient, there is little justification for its supplementation as a treatment for ADHD in children with normal levels of this mineral. If iron levels are low, a health care provider can determine whether replacement is needed.

Cough associated with ACE inhibitor use

One preliminary clinical study suggested that iron supplementation may soothe and even prevent cough associated with a class of medications known as angiotensin-converting enzyme (ACE) inhibitors, including enalapril (Vasotec), captopril (Capoten), and lisinopril (Zestril or Prinivil). ACE inhibitors are medications commonly used to treat high blood pressure and heart failure, but dry cough is a side effect that leads many people to discontinue their use. Despite this encouraging information, it is premature to conclude that taking iron with ACE inhibitors to reduce dry cough is safe or effective.

Plus, it is important to note that taking ACE inhibitors at the same time as iron may diminish the absorption of this nutrient. Therefore, if used together, the two should be taken at least two hours apart. Also, iron is associated with some risk for heart disease. For this reason, it should not be used by individuals with high blood pressure or heart failure without the consent and supervision of a doctor.

Infants and children

Iron deficiency is a significant public health problem in young children due to their high iron requirements, and iron supplements are therefore often recommended by health care providers. Iron deficiency may increase the risk of lead poisoning in children. However, the use of iron supplementation in lead poisoning is reserved for those individuals who are truly iron deficient or for those individuals with continuing lead exposure, such as continued residence in lead-exposed housing. Do not give iron supplements to infants or children under 18 unless under the supervision of a doctor.

Dietary Sources

The best dietary sources of iron are liver and other organ meats, lean red meat, poultry, fish, and shellfish (particularly oysters). Iron from these sources is readily absorbed in the intestines.

Other sources of iron include dried beans and peas, legumes, nuts and seeds, whole grains, dark molasses, and green leafy vegetables. However, iron from these sources must be accompanied by certain nutrients for proper absorption. For example, vitamin C helps the absorption of this type of iron while calcium (including all dairy products), bran, tea, and unprocessed whole grain products block its absorption.

In the U.S., grain products such as breads and cereals are fortified with iron to help increase amount in our diet.

Available Forms

Ferrous sulfate is the most common type of iron supplement. Other available forms include ferrous fumarate, ferrous succinate, ferrous gluconate, ferrous lactate, ferrous glutamate, ferric ammonium citrate, and ferrous glycine.

In severe cases of anemia from low levels of iron, or if there is rapid blood loss leading to iron deficiency, iron and blood will be administered intravenously (IV or in the veins) in a hospital setting.

How to Take It

Recommendations for iron are provided in the Dietary Reference Intakes (DRIs) developed by the Institute of Medicine of the National Academy of Sciences.

Infants and children (under 18 years of age)

Do not give iron supplements to infants or children under 18 unless under the supervision of a doctor.

For infants 7 – 12 months: The recommended dietary allowance is 11 mg daily.

For children 1 – 3 years: The recommended dietary allowance is 7 mg daily.

For children 4 – 8 years: The recommended dietary allowance is 10 mg daily.

For children 9 – 13 years: The recommended dietary allowance is 8 mg daily.

For male children 14 – 18 years: The recommended dietary allowance is 11 mg daily.

For female children 14 – 18 years: The recommended dietary allowance is 15 mg daily.

Iron in human breast milk is well absorbed by infants. It is estimated that infants can use greater than 50% of the iron in breast milk as compared to less than 12% of the iron in infant formula. The amount of iron in cow's milk is low, and infants poorly absorb it. Feeding cow's milk to infants also may result in gastrointestinal bleeding. For these reasons, cow's milk should not be fed to infants until they are at least 1 year old. The American Academy of Pediatrics (AAP) recommends that infants be exclusively breast fed for the first 6 months of life. Gradual introduction of iron-enriched solid foods should complement breast milk from 7 - 12 months of age. Infants weaned from breast milk before 12 months of age should receive iron-fortified infant formula. Infant formulas that contain from 4 -12 mg of iron per liter are considered iron-fortified.

Adult

For male adults 19 – 50 years: The recommended dietary allowance is 8 mg daily.

For female adults 19 – 50 years: The recommended dietary allowance is 18 mg daily.

For adults 51 years and older: The recommended dietary allowance is 8 mg daily.

For pregnant females ages 14 – 50 years: The recommended dietary allowance is 27 mg daily.

For lactating females ages 14 – 18 years: The recommended dietary allowance is 10 mg daily.

For lactating females ages 19 – 50 years: The recommended dietary allowance is 9 mg daily.

Precautions

Because of the potential for side effects and interactions with medications, dietary supplements should be taken only under the supervision of a knowledgeable health care provider.

The most common side effect from iron supplements is stomach upset, including discomfort, nausea, diarrhea, constipation, and heartburn.

Although not entirely clear, there may be an association between high iron stores and risk of heart disease, cancer (such as breast cancer), and Alzheimer's disease. Similarly, for those with inflammatory bowel disease (Crohn's disease and ulcerative colitis) the areas of the bowel that are inflamed appear to have higher amounts of iron. This is thought to be because iron acts as a pro-oxidant, stimulating the damaging effects in the body of substances known as free radicals.

Iron overload disease, although most commonly an inherited condition called hemochromatosis, may occur in people who consume excessive amounts of iron over a long period of time. Symptoms include skin discoloration, diabetes, and liver damage, among other potential complications. The U.S. Food and Drug Administration (FDA) has established that taking up to 45 mg of iron per day is safe. However, safety for amounts higher than 45 mg per day is not known. Severe iron overdose occurs when amounts of iron equivalent to 50 -100 times greater than the recommended dietary dose are ingested. Such iron toxicity can lead to destruction of cells in the gastrointestinal tract, which can cause vomiting, bloody diarrhea, and even death. Given the severity of potential adverse effects from excessive iron, supplements should be kept in childproof bottles and out of the reach of children.

Intravenous (into the veins) iron, administered in the case of severe anemia in a hospital setting, can lead to headache, fever, swollen lymph nodes, painful joints, hives, worsening of rheumatoid arthritis, and in rare instances a life-threatening allergic reaction known as anaphylaxis.

Possible Interactions

If you are currently being treated with any of the medications discussed below, you should not use iron without first talking to your health care provider.

Iron may interfere with the absorption of many different medications. For this reason, it is best to take iron supplements at least 2 hours before or 2 hours after taking medications. This is particularly true for the medications listed below.

The following medications may reduce the absorption of iron:

Cholestyramine and Colestipol -- These are two cholesterol-lowering medications known as bile acid sequestrants.

Medications used to treat ulcers or other stomach problems -- Examples of anti-ulcer medications include cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), and nizatidine (Axid). These medications belong to a class of drugs known as H2 receptor blockers. They change the pH in the stomach and subsequently alter the absorption of iron. It is possible that this effect could occur with other antiulcer medications including antacids and proton pump inhibitors, including omeprazole (Prilosec).

Iron decreases the absorption of the following medications:

Tetracyclines -- These are a class of antibiotics that include doxycycline (Vibramycin), minocycline (Minocin), and tetracycline (Sumycin).

Quinolones -- These are a class of antibiotics that include ciprofloxacin (Cipro), norfloxacin (Noroxin), and levofloxacin (Levaquin).

ACE inhibitors -- These are a class of medications used to treat high blood pressure. Examples include captopril (Capoten), enalapril (Vasotec), and lisinopril (Zestril or Prinivil).

Iron may reduce the effectiveness or blood levels of the following medications:

Carbidopa and Levodopa -- Iron lowers blood levels of carbidopa and levedopa (Sinemet ) but it is unclear whether these changes lower the effectiveness of the drugs.

Levothyroxine -- Iron may decrease the effectiveness of this thyroid replacement hormone. A health care provider will monitor thyroid function closely in those taking iron supplements with thyroid medications, including Armour Thyroid and levothyroxine (Synthroid).

Iron levels may be increased by:

Birth control medications -- Birth control medicines, or oral contraceptives, may increase iron levels, thereby decreasing the need for extra iron. Be careful if you are taking oral contraceptives not to take multiple vitamins that contain iron.

Supporting Research

Akerele JO, Okhamafe AO. Influence of oral co-administered metallic drugs on ofloxacin pharmacokinetics. J Antimicrob Chemother. 1991;28:87-94.

Balfour JA, Wiseman LR. Moxifloxacin. Drugs. 1999;57(3):363-374.

Baumgaertel A. Alternative and controversial treatments for attention-deficit/hyperactivity disorder. Pediatr Clin of North Am. 1999;46(5):977-992.

Belton N. Iron deficiency in infants and young children. Professional Care of Mother and Child. 1995;5:69–71.

Brouwers J. Drug interactions with quinolone antibacterials. Drug Safety. 1992;7(4):268-281.

Campbell NR, Hasinoff BB, Meddings JB, Anderson WD, Robertson S, Granberg K. Ferrous sulfate reduces cimetidine absorption. Dig Dis Sci. 1993;38(5):950-954.

Christen Y. Oxidative stress and Alzheimer disease. Am J Clin Nutr. 2000;71(suppl):621S-629S.

Dayal M, Barnhart KT. Noncontraceptive benefits and therapeutic uses of the oral contraceptive pill. Semin Reprod Med. 2001;19(4):295-303.

Dietary Guidelines for Americans 2005. Rockville, MD: US Dept of Health and Human Services and US Dept of Agriculture; 2005.

Domellof M. Iron requirements, absorption and metabolism in infancy and childhood. Curr Opin Clin Nutr Metab Care. 2007;10(3):329-35.

Duffy SJ, Biegelsen ES, Holbrook M, et al. Iron chelation improves endothelial function in patients with coronary artery disease. Circulation. 2001;103(23):2799-2804.

Fleming DJ, Jacques PF, Dallal GE, et al. Dietary determinants of iron stores in a free-living elderly population: the Framingham Heart Study. Am J Clin Nutr. 1998;67:722–733.

The Food and Nutrition Information Center. National Agricultural Library (NAL), United States Department of Agriculture's (USDA) Agricultural Research Service (ARS).

Gera T, Sachdev HP, Nestel P, Sachdev SS. Effect of iron supplementation on haemoglobin response in children: systematic review of randomised controlled trials. J Pediatr Gastroenterol Nutr. 2007;44(4):468-86.

Hercberg S, Preziosi P, Galan P. Iron deficiency in Europe. Public Health Nutr. 2001;4(2B):537-545.

Hinton PS, Giordano C, Brownlie T, Haas JD. Iron supplementation improves endurance after training in iron depleted, nonanemic women. J Appl Physiol. 2000;88(3):1103-1111.

Institute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press. January 9, 2001.

Jensen JT, Speroff L. Health benefits of oral contraceptives. Obstet Gynecol Clin North Am. 2000;27(4):705-721.

Kara M, Hasinoff BB, McKay DW, et al. Clinical and chemical interactions between iron preparations and ciprofloxacin. Br J Clin Pharmacol. 1991;31(3):257-261.

Killip S, Bennett JM, Chambers MD. Iron deficiency anemia. Am Fam Physician. 2007;75(5):671-8.

Lee SC, Park SW, Kim DK, Lee SH, Hong KP. Iron supplementation inhibits cough associated with ACE inhibitors. Hypertension. 2001;38(2):166-170.

Li RC, Lo KN, Lam JS, et al. Effects of order of magnesium exposure on the postantibiotic effect and bactericidal activity of ciprofloxacin. J Chemother. 1999;11(4):243-247.

Liehr JG, Jones JS. Role of iron in estrogen-induced cancer. Curr Med Chem. 2001;8(7):839-849.

Lih-Brody L, Powell Sr, Collier KP, et al. Increased oxidative stress and decreased antioxidant defenses in mucosa of inflammatory bowel disease. Dig Dis Sci. 1996;41(10):2078-2086.

Mittal R, Marwaha N, Basu S, Mohan H, Ravi Kumar A. Evaluation of iron stores in blood donors by serum ferritin. Indian J Med Res. 2006;124(6):641-6.

Neuvonen PJ. Interactions with the absorption of tetracyclines. Drugs. 1976;11(1):45-54.

Okhamafe AO, Akerele JO, Chukuka CS. Pharmacokinetic interactions of norfloxacin with some metallic agents. Int J Pharmaceutics. 1991;68:11-16.

Say AE, Gursurer M, Yazicioglu MV, Ersek B. Impact of body iron status on myocardial perfusion, left ventricular function, and angiographic morphologic features in patients with hypercholesterolemia. Am Heart J. 2002;143(2):257-264.

Schaefer JP, Tam Y, Hasinoff BB, et al. Ferrous sulphate interacts with captopril. Br J Clin Pharmacol. 1998;46(4):377-381.

Sempos C, Looker AC, Gillum RE, McGee DL, Vuong CV, Johnson CL. Serum ferritin and death from all causes of cardiovascular disease: The NHANES II Mortality Study. Ann Epidemiol. 2000;10(7):441-448.

Sever Y, Ashkenazi A, Tyano S, Weizman A. Iron Treatment in children with attention deficit Hyperactivity disorder: a preliminary report. Neuropsychobiology. 1997; 35:178-180.

Shakir KM, Chute JP, Aprill BS, Lazarus AA. Ferrous sulfate-induced increase in requirement for thyroxine in a patient with primary hypothyroidism. South Med J. 1997;90(6):637-639.

Sturniolo GC, Mestriner C, Lecis PE, et al. Altered plasma and mucosal concentrations of trace elements and antioxidants in active ulcerative colitis. Scand J Gastroenterol. 1998;33:644-649.

Tappel A. Heme of consumed red meat can act as a catalyst of oxidative damage and could initiate colon, breast and prostate cancers, heart disease and other diseases.Med Hypotheses. 2007;68(3):562-4.

Torkos S. Drug-nutrient interactions: a focus on cholesterol-lowering agents. Int J Integrative Med. 2000;2(3):9-13.

Tyrer LB. Nutrition and the pill. J Reprod Med. 1984;29(7 Suppl):547-550.

Tzonou A, Lagiou P, Trichopoulou A, et al. Dietary iron and coronary heart disease: a study from Greece. Am J Epidemiol. 1998;147:161–166.

Review Date:
5/14/2007
Reviewed By:
Ernest B. Hawkins, MS, BSPharm, RPh, Health Education Resources; and Steven D. Ehrlich, N.M.D., private practice specializing in complementary and alternative medicine, Phoenix, AZ. Review provided by VeriMed Healthcare Network.

A.D.A.M. Copyright

adam.com

Vitamins

FitSugar — Wed, 08 Oct 2008 17:35:00 -0700

In This Report

Highlights
Introduction
Carotenoids
Phytochemicals
Healthy Foods
Dietary Health Benefits
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Cancer

Growing evidence suggests that vitamins and micronutrients, especially from foods, may play important roles in the prevention or treatment of certain cancers:

One study found that the risk of prostate cancer risk dropped as consumption of vegetables high in vitamin C, such as broccoli and bell peppers, rose.
A diet high in cruciferous vegetables has been found to reduce the risk of kidney cancer; low consumption of cruciferous vegetables increases the risk.

On the other hand, high amounts of folic acid (a B vitamin) may be associated with colorectal cancer, and beta-carotene supplements are associated with increased lung cancer risk in smokers and people exposed to asbestos.

Macular Degeneration

In 2007, the National Eye Institute recommended that people with intermediate or advanced macular degeneration in one eye take a vitamin formula shown to reduce the risk of macular degeneration in the other eye by 25%. The formula contains vitamin C, vitamin E, beta-carotene, and zinc.

Osteoporosis

Vitamin K is widely used in Japan to treat osteoporosis, and studies suggest it also may be effective in treating rheumatoid arthritis.

Heart Disease

Although people with high levels of homocysteine are prone to developing blood clots in their arteries and veins, a 2007 study found that lowering homocysteine with B vitamins and folic acid does not reduce the incidence of deep vein thrombosis (DVT). A 2007 trial in adults with stable coronary artery disease found that lowering homocysteine levels 33% with folic acid and other B vitamins had no effect on arterial inflammation, meaning that lower levels were unlikely to offer protection against heart attack or stroke.

Introduction

Vitamins do not share a common chemistry, but they do share certain characteristics. They are all organic nutrients that are necessary in small amounts for normal metabolism and good health. Your diet or supplements provide most vitamins. The body can manufacture only three vitamins (D, K, and the B vitamin biotin) from nondietary sources. Unlike carbohydrates, fats, and proteins, vitamins are not sources of energy. Instead, vitamins are chemical partners for the enzymes involved in the body's metabolism, cell production, tissue repair, and other vital processes.

Vitamins are either fat soluble or water soluble. The fat-soluble vitamins, which include A, D, E, and K, are absorbed by the body using processes that closely parallel the absorption of fat. They are stored in the liver and used up by the body very slowly. The water-soluble vitamins include C and the B complex vitamins. The body uses these vitamins very quickly. Excess amounts are eliminated in urine.

The Recommended Daily Allowance (RDA) for vitamins, set by the Food and Nutrition Board of the National Academy of Sciences-National Research Council, has been used for years as a guide for determining the amount of vitamins needed for a healthy diet. The RDA refers to an estimate of the average daily requirement. It is not completely adequate, however, for informing people about the amounts of vitamins they may need.

The RDA is gradually being enhanced using a new standard called the Dietary Reference Intake (DRI). The DRI is based on the following ratings, which will eventually appear on labels:

The recommended daily allowance (RDA). This is the current rating on most vitamins.
The estimated average requirement (EAR). This is the amount adequate for 50% of all people, which will be put on labels when it can be calculated.
Adequate intake (AI). This is an amount that will be used if there is insufficient data to calculate the EAR.
Tolerable upper intake level (UL). This is the maximum dose likely to be safe in nearly all individuals. It will be included on labels if this amount is known.

Food and supplement labels now typically list the Daily Value (DV). This is the percentage of the amount of a nutrient that experts believe a person needs in their daily diet. On food labels it is usually based on one serving size for a person who takes in 2,000 calories a day.

Regulation of dietary supplements by the U.S. Food and Drug Administration (FDA) is a complex issue.

Labels on vitamins and other dietary supplements now include nutrient information and list all ingredients, including identifying parts of plants from which ingredients may be taken. Unlike the labels for drugs, however, labels for vitamins and supplements may not claim to prevent or treat any specific disease. Labels for vitamins and supplements include one of the following:

Health claim -- description of how the substance may reduce the risk of a health-related condition
Nutrient claim -- description of the amount of the nutrient in the product or
Structure or function claim -- description of how the product may affect organs or systems of the body, without claiming to prevent or treat specific disease

The quality of dietary supplements depends on the manufacturer and is not ensured by FDA. The U.S. government does not require that supplements be standardized, meaning that the amounts or quality of nutrients may vary depending on the batch. So, more expensive supplements are not necessarily better than the less expensive ones. Government regulations are in the process of catching up to the boom in the supplement industry. In the meantime, some companies voluntarily adhere to rigorous quality controls, while others do not.

The U.S. Pharmacopeia (USP), an independent organization that sets quality standards for drugs, has also implemented standards for vitamins. Consumers may look for the USP label on products of companies that adhere to these standards. USP verification means the following:

What is in the bottle matches what is listed on the label.
There are no harmful levels of contaminants.
The supplement will be absorbed properly into the body.
It has been produced according to good manufacturing standards.

Before selling any supplement introduced after 1994, manufacturers must submit information as to why the product is considered safe for people. The FDA may refuse to allow it on the market if it finds the evidence insufficient. The FDA does not require manufacturers to provide any scientific evidence that dietary supplements are safe and effective before a product is sold (unlike drugs, which must be proven both safe and effective through clinical trials). If a supplement causes side effects in people once it is for sale, the government may place restrictions on the supplement or withdraw it from the market. The FDA may also withdraw products from the market if their labels are misleading or false.

About 30% of Americans take at least one vitamin or mineral supplement daily. In a large study that examined the death rates of 11,000 people, however, there was no difference in mortality rate between those who took vitamin supplements and those who didn't. Most people who have a healthy diet do not need vitamins, but there are some exceptions.

Pregnant and Breast-Feeding Women. Women who are pregnant or who are breast-feeding generally need additional vitamins. Vitamins B6, B12, and folic acid are particularly important. Women who are vegetarians must be sure to avoid deficiencies, which can harm their offspring. Folic acid reduces the risk for neural tube defects and possibly facial abnormalities, such as cleft palate. Studies also show that low folate levels during pregnancy are associated with low birth weight, a risk factor for the development of cardiovascular disease in adulthood. Multivitamins that contain folic acid also appear to be somewhat protective. A woman's best approach is to take extra folic acid plus multivitamin supplements (which have additional benefits), starting them before becomming pregnant.

The human body stores several years' worth of vitamin B12, so nutritional deficiency of this vitamin is extremely rare. Although, people who follow a strict vegetarian diet and do not consume eggs or dairy products may require vitamin B12 supplements.

Pregnant women with healthy diets may have low folate levels and need to take supplements. Requirements are as follows:

The recommended daily allowance (RDA) for folic acid prior to conception and during pregnancy is 400 mcg.
During breast-feeding 260 - 280 mcg is recommended.

The following vitamins may have some value for pregnant women:

Choline, another vitamin B, is also essential for pregnant (450 mg) and nursing women (550 mg). Choline plays a key role in brain development. Not getting enough during pregnancy can lead to memory and cognitive defects in the baby. Choline supplements can also lessen the cognitive defects of prenatal alcohol exposure.
Vitamin B6 may help improve morning sickness.
Vitamin C may reduce the risk of urinary tract infections during pregnancy.
Vitamin D may help prevent preeclampsia.
One study also suggested that if pregnant women took vitamin K supplements, their infants might not need the required injection of this vitamin after birth, but supplements of vitamin K during pregnancy are not currently recommended.

Some women have low vitamin A reserves in their liver. It is important to note, however, that too much vitamin A significantly increases the risk for birth defects. Daily amounts of 10,000 IU (international units) of vitamin A in supplements and food (an amount not far above the RDA level) can pose a danger. Experts recommend that pregnant women take in no more than 8,000 IU per day and avoid eating liver.

Infants and Children. Infants who are breast-fed by healthy mothers receive enough vitamins except, in some cases, vitamins K and D. Human milk has low levels of K, and the newborn's immature intestinal tract may not produce enough of the baby's own supply. Most babies are given an injection of this vitamin at birth. Infants being breast-fed by malnourished women or those who lack sufficient exposure to sunlight may be deficient in vitamin D. In these cases, supplements of 200 - 300 IU are recommended. Formulas are required to contain sufficient vitamins and minerals. One study suggests that vitamin supplements for infants under 1 year of age may help protect them from developing type 1 diabetes later on. Beyond infancy, most American children receive all the vitamins they need from their diet unless they are living in severely deprived circumstances.

Smokers. Smoking interferes with absorption of several vitamins, importantly vitamins C and D. In one study nearly 25% of female smokers and 31% of male smokers were deficient in vitamin C. Smoking can interfere with the metabolims of vitamin D, resulting in poor muscle function. Taking high doses of antioxidant vitamins, however, may actually be harmful in smokers, especially beta carotene. Instead of taking supplements, most smokers should be sure their diets are rich in fresh fruits and vegetables and whole grains. Of course, smoking cessation is the most important intervention of all.

Click the icon to see an image of sources for vitamin C.

Alcoholics. Alcoholics often suffer from multiple vitamin deficiencies. The most dangerous deficiencies are from vitamins B1 (thiamin), folic acid, B6 (pyridoxine), B2 (riboflavin), and vitamin C. Low levels of B6 are associated with increased risk of colorectal cancer in men who drink large amounts of alcohol.

Overweight Adults. Overweight and obesity causes many problems that often result in metabolic syndrome or type 2 diabetes. Evidence suggests that isoflavones can help regulate cholesterol levels and reduce body weight and fat mass. Because some medications used to control blood sugar levels reduce folic acid and vitamin B12, some people may need vitamin supplements.

People Who Have Had Gastric Bypass Surgery. Vitamin deficiency is a recognized complication of gastric bypass surgery. Women, African-Americans of both sexes, and adults who have had laparoscopic Roux-en-Y bypass surgery are at highest risk. The deficiency is treated with water-soluble vitamin supplements.

Strict Vegetarians. Strict vegetarians need supplements of vitamin B12, unless they get enough of it from fortified cereals and other grain products.

Dieters and Vegetarians. People on weight-reduction diets with less than 1,000 calories a day should probably take a multivitamin and should also check regularly with a physician.

Vegetarians may need riboflavin, vitamin B12, and vitamin D supplements. Vegans, who do not eat dairy or eggs as well as meat, may be at further risk for vitamin A deficiencies if they do not also have plenty of dark colored fruits and vegetables. Those who eat eggs and dairy products need only watch their iron levels.

Deficiencies in vegetarian children may be particularly harmful. (One study, for example, reported that adolescents who had been on macrobiotic diets before age 6 and were deficient in vitamin B12 scored lower on psychological tests.) Pregnant and breast-feeding women who are vegetarians must be sure to have sufficient vitamins. Of special note, maternal deficiencies in vitamin B12 may cause delayed growth and neurologic problems in their newborns.

Click the icon to see an image of sources for vitamin D.

Older Adults. Deficiencies of vitamins and important minerals have been observed in almost a third of elderly people. Often their dietary habits slip and they fail to eat balanced meals regularly. Multiple drug regimens may prevent absorption of some vitamins. Elderly people, particularly if they are not exposed to sunlight, may be deficient in vitamin D. They also may have low levels of important B vitamins. (Older adults showing signs of dementia should be checked for B12 deficiencies as well as other disorders causing mental disturbances.) One study reported that the immune systems of elderly people may benefit from higher levels of vitamin E than the daily recommended dosage. It should be noted, however, that metabolism slows down as a person ages, and in elderly people it takes the liver longer to eliminate drugs and vitamins from the body. The effect of some vitamin supplements, therefore, may be intensified. Dosage levels of vitamin A, for instance, which might be harmless in a younger adult, could be toxic in an elderly patient. Nevertheless, experts are increasingly recommending extra vitamin and mineral supplements for older people.

People Who Need to Avoid Sunlight. People who need to avoid sunlight or are housebound, and whose diet is low in foods that contain vitamin D should take supplements. People with darker skin are at higher risk for deficiencies than those with whiter skin. (Note: vitamin D is toxic in high doses, and no one should exceed the recommended daily intake of vitamin D except under the direction of a physician.)


Benefits	Essential for growth, bone development, night vision, reproduction, and healthy skin.
Recommended daily allowance (RDA) or dietary reference intake (DRI) (mcg = micrograms, mg = milligrams, IU = international units)	Vitamin A RDA and Upper Limit (when toxicity is risk) are the following: For children: 1,000 IU ages one to three (upper limit is 2,000 IU); 1,333 IU ages 4 - 8 (upper limit is 3,000 IU); and 2,000 IU for 9 - 13 (upper limit is 5,665 IU). For nonpregnant women: 2,330 IU ages 14 through adulthood. (Upper limit is 9,335 IU for ages 14 - 18 and 10,000 IU for women over 19.) For pregnant women: 2,500 IU for pregnant women under 18; 2,565 IU for pregnant women over 19. (Upper limit is 9,335 IU for ages 14 - 18 and 10,000 IU for women over 19. It should be noted that some experts recommend 8,000 IU as the upper limit during pregnancy.) Warning: Use of the topical acne medication tretinoin, a vitamin A derivative, during pregnancy can cause birth defects. For nursing women: 4,000 IU for nursing mothers under 18; 4,335 IU for nursing mothers over 19. (Upper limit is 9,335 IU for ages 14 - 18 and 10,000 IU for women over 19.) For men: 3,000 IU ages 14 - 18; 3,000 IU for ages 19 and above. (Upper limit is 10,000 IU.) Note: In determining the daily vitamin A allowance, experts also take note of provitamins, such beta carotene, that convert to vitamin A. Some experts recommend 3 - 6 mg of beta-carotene. Vitamin A is also now being measured with a new unit called the Retinol Activity Equivalent (RAE or RE). One RE is equal to 1 mcg. Retinol is the most active form of vitamin A and it is also converted in the liver from carotenoids. One RE is equal to 12 mcg of beta-carotene or 24 mcg of alpha-carotene or beta-cryptoxanthin).
Foods containing the vitamin	Animal products, such as liver, dairy products, eggs, and fish liver oil. Provitamin A carotenoids are also found in dark red, green, and yellow vegetables and fruits. Requires some dietary fat to be absorbed.
Effects of deficiencies	Skin disorders, severe diarrhea, and eye damage. In less developed countries severe deficiencies cause blindness in 250,000 children each year. Diets low in vitamin A may also increase the risk of developing cancer. Low dietary intake of vitamin A has been associated with impaired lung function in children.
People at risk for deficiencies	Preschool children and any child with inadequate intake of protein, calories, and zinc. Iron deficiency may also impair metabolism of vitamin A. People with asthma. People with serious disorders in the intestine, liver or pancreas, such as cystic fibrosis, steatorrhea, biliary obstruction, inflammatory bowel disease, cirrhosis, and others. People who have undergone Roux-en-Y gastric bypass surgery. Vegans (vegetarians who do not eat eggs and dairy). Such individuals should be sure to have plenty of deep-colored fruits and vegetables. People who abuse alcohol. It should be noted, however, that people with alcoholism may be at risk for vitamin A deficiency, but a combination of high-dose vitamin A and alcohol may cause toxic effects in the liver. Healthy adults usually have a year's store of vitamin A in the liver, so temporary nutritional deficiencies or problems with fat absorption are unlikely to cause serious vitamin A deficiency problems.
Toxicities	Very toxic when taken in high-dose supplements for long periods of time. Symptoms of overdose include dizziness, nausea, vomiting, headache, skin damage, mental disturbances, and, in women, infrequent periods. Can affect almost every part of the body, including eyes, bones, blood, skin, central nervous system, liver, and genital and urinary tracts. Severe toxicity can cause blindness and may even be life threatening. In children, chronic overdose can cause fluid on the brain and as well as adult complications. High consumption of vitamin A may also increase the risk of gastric cancer and the risk of osteoporosis and fractures in both men and women. Pregnant women who take amounts not much higher than RDA levels increase the risk for birth defects in their children. Liver damage can occur in children who take RDA-approved adult levels over prolonged periods of time or in adults who take as little as five times the RDA-approved amount for 7 - 10 years.


	B Vitamins: General Information	Vitamin B1 (thiamin)
Benefits	The B vitamins have a wide and varied range of functions in the human body. Most B vitamins are involved in the process of converting blood sugar into energy.	Essential for converting blood sugar into energy and is involved in metabolic activities in nerves, heart, and muscles and in the production of red blood cells.
Recommended daily allowance (RDA) or dietary reference intake (DRI) (mcg = micrograms, mg = milligrams, IU = international units)		RDA is 1.2 mg per day for men and 1.1 mg for women.
Foods containing the vitamin		Best source is pork and good sources are dried fortified cereals, oatmeal, corn, nuts, cauliflower, and sunflower seeds. Supplements for people with normal diets and health are unnecessary.
Effects of deficiencies	Deficiencies are uncommon in the U.S., but when they occur, they usually involve several B vitamins, since many of them come from the same food groups.	Severe vitamin B1 deficiency is known as beriberi. It can cause visual disturbances, paralysis, staggering, loss of sensation in the legs and feet, psychosis, and congestive heart failure.
People at risk for deficiencies	Alcohol interferes with these vitamins, and some of the physical and mental problems that alcoholics experience may be attributed to a deficiency of B vitamins. Elderly people are also at risk for deficiencies because of inadequate diets and potential interference with B-vitamin absorption by medications. Deficiencies can occur in severely malnourished people or in those receiving long-term dialysis or intravenous feeding. Vegetarians may be at risk.	See general vitamin B description.
Toxicities	Because the B vitamins are water-soluble and eliminated in the urine, toxic reactions from oral administration of most of them are extremely rare. (Exceptions are niacin and B6.) It should be noted that substances known as B15 (pangamic acid) and B17 (laetrile) are neither vitamins nor nutrients; both chemicals are highly dangerous and have no proven nutritional or health value.	No toxic effects have been reported from thiamin.


	Vitamin B2 (riboflavin)	Vitamin B3 (niacin) also known as nicotinic acid	Vitamin B5 (Pantothenic Acid)
Benefits	Important in the production of energy.	Helps break down blood sugar for energy. Acts as a vasodilator, widening blood vessels and increasing blood flow. May be prescribed for improving cholesterol levels.	Important for metabolism of fats, carbohydrates, and proteins, as well as production of steroid hormones and other important chemicals.
Recommended daily allowance (RDA) or dietary reference intake (DRI) (mcg = micrograms, mg = milligrams, IU = international units)	DRI is 1.7 mg.	DRI is 20 mg.	Adequate intake (AI) is 4 - 7 mg.
Foods containing the vitamin	Liver, dried fortified cereals, dairy products, fish. Some dark green vegetables. Supplements for people with normal diets and health are unnecessary.	Mackerel, swordfish, chicken, veal, dried fortified cereals, pork, salmon, and beef liver. Supplements are unnecessary in people with normal health and diets.	Whole grains, beans, milk, eggs, and liver. Supplements are unnecessary in people with normal health and diets.
Effects of deficiencies	Deficiencies affect the skin and mucous membranes and can cause cracks on the lips or corners of the mouth, eczema of the face and genitals, a burning sensation on the tongue, eye irritation. May contribute to anemia when iron levels are low and contribute to elevated levels of homocysteine, a heart risk factor.	Deficiency causes pellagra; symptoms can include eczema, intestinal and stomach distress, depression, headache, thinning of the hair, and excess saliva production.	Deficiency is unlikely except in company with other B vitamin deficiencies. Symptoms include abdominal distress, burning sensation in the heels, and sleep problems.
People at risk for deficiencies	See general vitamin B description.	Alcoholics and any malnourished persons.	Alcoholics and any malnourished persons.
Toxicities	Until recently, no toxic effects had been reported even from large doses of riboflavin. However, one study indicated that high consumption of vitamin B2 might increase the risk of stomach cancer. More research is needed. (In the same study, vitamins B1, B3, and B6 were protective.)	Even mildly high doses of niacin can cause hot flushing of the face and shoulders, headache, itchiness, and stomach problems. Some report heart disturbances and temporarily lowered blood pressure. Large doses may produce ulcers, gout, diabetes, and liver damage, which are usually reversed when high doses are discontinued.	Although no toxicity has been reported in humans, high dosages have caused liver damage in rats.


	Vitamin B6 (pyridoxine)	Vitamin B12 (cobalamin)
Benefits	Has an effect on over 60 proteins in the body, importantly, those that play a role in the nervous system, in red and white blood cell production, and in heart disease.	Essential for the production of blood cells, manufacturing genetic material, and for healthy functioning of the nervous system. New evidence suggests that high levels of B12 may protect against colon and rectal cancer.
Recommended daily allowance (RDA) or dietary reference intake (DRI) (mcg = micrograms, mg = milligrams, IU = international units)	RDA is 1.3 mg in adults under 50 and 1.7 mg for older men and 1.5 for older women. (Some experts recommend 3 to 6 mg for people who need heart protection.) Upper limit is 100 mg for adults.	RDA is 2.4 mcg in men and nonpregnant women, 2.6 mcg in pregnant women, and 2.8 mcg in nursing mothers.
Foods containing the vitamin	Meats, oily fish, poultry, whole grains, dried fortified cereals, soybeans, avocados, baked potatoes with skins, watermelon, plantains, bananas, peanuts, and brewer's yeast.	The only natural dietary sources are animal products, including 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.
Effects of deficiencies	Increased levels of homocysteine, associated with heart disease and possibly Alzheimer's disease. Skin problems and nervous system disorders, including impaired memory and concentration. Increased risk for kidney stones. One study found a correlation between vitamin B6 deficiency and inability to conceive or carry a child to term. In unborn children, some evidence shows that lack of vitamin B6, in addition to vitamin B12 and folic acid, may be responsible for defects such as cleft lip and palate and spina bifida. Supplementation with these vitamins is advised during pregnancy. Note: People who have been taking more than 50 mg for some time and stop suddenly are at risk for a so-called rebound deficiency. When people stop, they should taper off slowly.	Deficiencies elevate homocysteine, a possible risk factor for heart disease and Alzheimer's disease. Increased risk of bone fractures. Abnormal gaits in the elderly. May cause severe depression, memory loss, instability, disorientation, and decreased reflexes, and possibly hearing loss. Children who are deficient may experience growth failure. Deficiencies in pregnant and breast-feeding women may cause neurologic harm in their offspring. A genetic defect that causes vitamin B12 deficiencies is responsible for pernicious anemia, a serious disorder that causes rapid heart rate, shortness of breath, dizziness, weakness, and fatigue. It must be treated with injections of vitamin B12 or else neurologic damage may occur.
People at risk for deficiencies	Alcoholics and any malnourished person. In rare cases, infants are born unable to metabolize pyridoxine; in such cases, seizures or convulsions can occur and vitamin B6 must be administered.	Alcoholics and any malnourished persons. Evidence suggests deficiencies may be caused by Helicobacter pylori (H. pylori) bacteria (a cause of ulcers). Nearly 30% of patients with inflammatory bowel disease have vitamin B6 deficiency, as well as low levels of iron and vitamin D. People who take the antibiotic isoniazid, high blood pressure medication hydralazine, and the drug penicillimine are at risk for vitamin B6 deficiency. The elderly and people with Crohn’s disease and those who have undergone ileal and ileocolonic resection may have trouble absorbing natural vitamin B12 and require supplements. Some evidence shows that patients with Parkinson’s disease treated with levodopa plus dopa decarboxylase inhibitor (DDC-i) and catechol-O-methyltransferase inhibitor (COMT-i) have low levels of both vitamin B12 and folate. As a result, they need to take supplements of these vitamins. Other studies have found that patients with diabetes treated with metformin, but not roziglitazone, are at risk for low levels of vitamin B12. Vitamin B12 deficiency is also common in patients with polyneuropathy. In up to one-third of patients, vitamin B12 deficiency is the sole or major contributing cause of their neuropathy. Treatment with vitamin B12 has a high success rate in improving the symptoms. Vegetarians are at higher risk for deficiencies.
Toxicities	Very high doses can cause nerve damage with symptoms of instability and numbness in the feet and hands, which may be permanent in some cases. Of specific concern are possible adverse effects on nerve development in the offspring of pregnant women who take large doses, such as for morning sickness.	There is no evidence of toxicity with this vitamin.


	Biotin (a B vitamin)	Choline (a B vitamin)	Folate, or Folic Acid, its synthetic form (a B vitamin)
Benefits	Involved in the production of amino acid proteins and fatty acids.	Essential for fetal brain development and for learning and memory.	Important for many metabolic processes in the body. It is used in the manufacturing of neurotransmitters (chemical messengers in the brain), in protecting the heart, and for synthesizing genetic materials (DNA) in the cells. It may improve blood flow.
Recommended daily allowance (RDA) or dietary reference intake (DRI) (mcg = micrograms, mg = milligrams, IU = international units)	There is no DRI for biotin; some experts suggest 30-100 mcg.	RDA 425 mg for nonpregnant women, 450 mg for pregnant women, and 550 mg for nursing women.	Supplements may be folate (natural) or folic acid (synthetic). Folic acid is nearly twice as potent as folate. DRI is 400 mcg (.4 mg) of folate for the general population, 600 mcg during pregnancy and 500 mcg while nursing. Women who are planning to be pregnant should certainly take 400 mcg of folic acid before conception, during pregnancy, and while nursing.
Foods containing the vitamin	Dietary sources are eggs, milk, liver, mushrooms, bananas, tomatoes, whole grains, nuts, and brewer's yeast. Also produced by bacteria in the intestines.	Peanuts, eggs, cauliflower, and meats, especially liver.	Avocado, bananas, orange juice, cold cereal, asparagus, green leafy vegetables, dried beans and peas, and yeast. Folic acid supplements are now added to commercial breads and cereals.
Effects of deficiencies	Deficiencies are almost unheard of.	Low levels during pregnancy increase risk of birth defects in newborns.	As with vitamins B6 and B12, deficiencies of folate elevate levels of homocysteine, an amino acid in the body that may increase the risk for heart disease, and possibly Alzheimer's disease. Folic acid supplements lower homocysteine levels, but with little or no impact on risk of atherosclerotic disease in the heart or in the peripheral arteries and veins. This suggests that homocysteine may be a marker of cardiovascular disease, rather than a cause. This being said, one 2007 study found that folic acid supplementation in patients with low folic acids levels substantially reduced the risk of a first stroke. Low levels during pregnancy increase risk of birth defects in newborns, and folic acid supplementation plays a key role in preventing birth defects. Folic acid deficiencies Deficiencies can also cause depression and megaloblastic anemia and impair concentration, memory, and hearing.
People at risk for deficiencies			Alcoholics, malnourished persons, people with conditions that disturb the small intestine, people taking certain drugs, particularly methotrexate. Other risk factors for deficiency: high-dose aspirin, smoking, treatment for seizures, taking oral contraceptives.
Toxicities		Excessive doses can cause intestinal problems, and there is also some concern that high doses can be carcinogenic.	Possible connection between high consumption of folate/folic acid and colorectal cancer now under exploration. Some link between high doses and central nervous system disorders, zinc deficiency, and seizures in epileptics. This risk appears to be low, but results indicate that megadoses should be avoided. High amounts in the elderly may mask symptoms of vitamin B12 deficiencies.


Benefits	Vitamin C is a water-soluble vitamin. Acts as an antioxidant (reduces harm from damaging chemical processes in the body). Essential for the production of collagen, the basic protein in bones, cartilage, tendons, and ligaments. A 2007 study found that vitamin C supplements can help prevent the development of complex regional pain syndrome following wrist fracture. Another study found that prostate cancer risk dropped as consumption of vegetables high in vitamin C, such as broccoli and bell peppers, rose. It may also protect against brochoconstriction during exercise in people with asthma. May help boost the immune system.
Recommended daily allowance (RDA) or dietary reference intake (DRI) (mcg = micrograms, mg = milligrams, IU = international units)	DRI is 75 mg (women) and 90 mg (men). (Smokers need an additional 35 mg.)
Foods containing the vitamin	Citrus fruits and juices, papayas, hot chili peppers, bell peppers, broccoli, potatoes, dark leafy greens, kale, red cabbage, cauliflower, cantaloupe, sweet potatoes, and Brussels sprouts. Orange juice is the most important source of vitamin C in the U.S., with frozen juice being the best source of the vitamin.
Effects of deficiencies	Scurvy is the primary deficiency disease. Affects most body tissues, particularly bones, teeth, and blood vessels. Early symptoms include tiredness, weakness, irritability, weight loss, and vague muscle aches. Later symptoms are bleeding gums, wounds that won't heal, rough skin, and wasting away of the muscles. Deficiencies may contribute to periodontal disease and gallstones. Low dietary intake of vitamin C has been associated with impaired lung function in children. Low intake may also increase lead levels in the blood.
People at risk for deficiencies	Deficiency has been uncommon in the U.S., usually occurring in the elderly, alcoholics, cancer patients, and some people on severely limited diets low in fresh fruits and vegetables. Surprisingly, however, studies now suggest that as many as 16% of middle-aged Americans, with the highest risk in smokers and middle aged men, are deficient in vitamin C. High doses of aspirin taken over a long period of time can interfere with vitamin C.
Toxicities	Tolerable upper limit is 2000 mg/day. High doses may cause headaches and diarrhea. Long-term high doses may increase risk for kidney stones. Ascorbic acid increases iron absorption so people with blood disorders, such as hemochromatosis, thalassemia, or sideroblastic anemia, should avoid high doses. Large doses may also thin blood and interfere with anticoagulant medications, blood tests used in diabetes, and stool tests. Rebound scurvy can occur after abrupt withdrawal from long-term large doses. This may affect infants or pregnant women who withdraw suddenly from high doses.


Benefits	Vitamin D is actually a single term for several hormones that are stored mainly in the liver and also in fat and muscle tissue. It is essential for the absorption of calcium into the bone and for normal bone growth.
Recommended daily allowance (RDA) or dietary reference intake (DRI) (mcg = micrograms, mg = milligrams, IU = international units)	RDA is 200 IU (5 mcg) per day for children and most adults to age 50, 400 IU (10 mcg) for people between ages 50 and 60, and 600 IU over age 70. and 1000 IU (15 mcg) for those over 70. People who are housebound, do not have sufficient exposure to sunlight, or are dark-skinned individuals, as well as breast-fed infants, should take need vitamin D supplements. The maximum tolerated dose after the age of 12 months is 2,000 IU/day
How the body gets the vitamin	There are two forms of vitamin D. Vitamin D3 is made in the body from a chemical reaction to the ultraviolet radiation in sunlight. Vitamin D2 is found in a few food sources, including vitamin D fortified milk, fatty fish, egg yolk, and liver.
Effects of deficiencies	Softening of the bones caused by low levels of calcium and phosphorous (called rickets in children and osteomalacia in adults). Also increases the risk for bone-related knee problems, and hip fractures in postmenopausal women. Associated with a higher risk for prostate cancer and breast cancer risk. Evidence suggests that vitamin D deficiency may be responsible for poor muscle strength after bone fracture. The deficiency is associated with high blood pressure and diabetes, but it is unknown whether supplementation with vitamin D impacts these diseases. Studies now suggest vitamin D plays a role in age-related macular degeneration (AMD), and that drinking milk with added vitamin D can help protect against AMD.
People at risk for deficiencies	Older people, particularly if they live in the North, who are underexposed to sunlight. Obesity may also increase risk. There is some concern, in fact, that vitamin D deficiency may be a growing problem in the US among younger adults as sunscreen use becomes widespread. Individuals at highest risk for vitamin D deficiency are those who assiduously avoid the midday sun, wear protective clothing, regularly use sunscreen, and have dark skin. Exposure to sunlight for about 15 - 20 minutes at mid-morning or mid-afternoon three times a week is recommended for most people who live in temperate climates.
Toxicities	Vitamin D is very toxic in high doses. In infants, daily amounts higher than 1,000 IU can cause mental and growth retardation, kidney failure, and death. In children and adults, daily amounts over 50,000 IU can cause weakness, anorexia, vomiting, diarrhea, and mental changes. Prolonged use of megadoses can cause calcification of soft tissue and life-threatening kidney failure. Low-calcium diets and withdrawal from the vitamin can usually reverse the side effects except for kidney failure.


	Vitamin E (Tocopherol or Tocotrienol)	Vitamin K
Benefits	A fat-soluble antioxidant vitamin that helps prevent cell membrane damage and may inhibit oxidation of LDL cholesterol (a process that increases its harmful effects on arteries). Researchers once thought that vitamin E might protect against cardiovascular disease. This theory has been debunked. However, a 2007 study found that vitamin E supplementation reduced the risk of deep vein thrombosis (DVT) in women at risk for, or with a history of, DVT. Vitamin E supplements have also been shown to produce a statistically significant decrease in menopausal hot flashes. There is also early evidence that vitamin E may protect against ovarian cancer.	The most important function of vitamin K is its role in blood clotting and prevention of bleeding. As a result, the vitamin may be able to help treat hepatoma, leukemia, and hepatocellular carcinoma, a form of liver cancer. The vitamin also contributes to maintaining healthy bones and healing fractures. Vitamin K is widely used in Japan to treat osteoporosis, and studies suggest it may be effective in treating rheumatoid arthritis.
Recommended daily allowance (RDA) or dietary reference intake (DRI) (mcg = micrograms, mg = milligrams, IU = international units)	RDA is 15 mg (22 IU) for all adults, including pregnancy women. Nursing mothers need 19 mg (28 IU). (Supplements should be taken along with some oil or fat to be absorbed.) Vitamin E is composed of 8 compounds (four tocopherols and four tocotrienols). Vitamin E is most often available as supplements of dl alpha tocopherol (a synthetic form). Other vitamin E compounds may prove to be more active than the standard synthetic supplement. They include natural vitamin E, called d-alpha- or RRR-alpha-tocopherol succinate (VES). Other vitamin E compounds of interest are tocotrienol and beta and gamma tocopherol. Supplements that contain a combination of some of these forms may be most beneficial.	RDA is 60 - 65 micrograms (women) and 70 - 80 micrograms (men).
Foods containing the vitamin	Vegetable oils (particularly wheat germ oil), sweet potatoes, turnip greens, mangos, avocados, nuts, sunflower seeds, and soybeans. Tocotrienol (a possibly beneficial form) is found in natural tropical oils. Palm oil sold in the US is refined and does not contain tocotrienol.	Best dietary sources are canola oil, cruciferous vegetables, and soybean oil. Good sources are beef liver, bran, and olive oil. Also produced by bacteria in the intestines.
Effects of deficiencies	Deficiencies have not been established.	Easy bruising, bleeding. May increase the risk of hip fractures in women.
People at risk for deficiencies	Low-birth weight infants. People who eat a low-fat diet. People with medical problems that impair fat absorption, such as Crohn's disease, cystic fibrosis, steatorrhea, liver diseases (such as cirrhosis). People with abetalipoproteinemia, a rare genetic disorder that impairs fat metabolism.	Deficiency may occur in patients who have problems absorbing fats, such as those with cirrhosis, people who are on long-term antibiotic therapy, or who are taking other medications, including cholestyramine, Dilantin, and phenobarbital. Some evidence suggests that more young people may be deficient than previously believed.
Toxicities	Upper level recommended is 1,500 IU of alpha tocopherol. Large doses may cause bleeding problems, particularly in people taking anti-clotting medications. Some research now indicates that vitamin E, like other antioxidants, may have pro-oxidant and damaging effects. Although vitamin E is one of the best studied vitamins, research has yielded conflicting results, and definitive conclusions about the benefits and toxicity of vitamin E have not yet been determined. In a major 2005 study, there was no significant difference in cancer rates between people who took 400 IU of vitamin E daily and those who did not, although those who took the supplement had a higher risk of heart failure. Additional studies also link high levels of vitamin E with a slightly increased risk of heart failure and death. On the other hand, studies show that vitamin E may reduce heart problems in high-risk patients such as certain people with diabetes.	Allergic-type responses, including rash and itching, to high doses have been reported. Those who are taking Coumadin, an anticoagulant, should not take vitamin K without consulting a physician. Vitamin K deficiency can cause anorexia, lethargy, growth retardation, bone loss, soft tissue calcification, and death.

Carotenoids

Carotenoids are a group of more than 700 fat soluble nutrients that produce the colors in foods such as carrots, pumpkins, sweet potatoes, tomatoes, and other deep green, yellow, orange, and red fruits and vegetables. Many are proving to be very important for health. Beta carotene is the most widely studied carotenoid, but others are proving to be of great interest. As with some, but not all, carotenoids, beta carotene is known as a provitamin A because it converts to the vitamin in the body.

They are categorized as either xanthophylls or carotenes according to their chemical composition.

Carotenes are hydrocarbons and most are found in yellow, orange, and red vegetables. They include beta and alpha carotene and lycopene.

Beta Carotene and other Provitamin A Carotenoids. Beta carotene, alpha-carotene, and beta-cryptoxanthin are carotenes that are converted into vitamin A or retinol (the active form of vitamin A) in the body. They are found in many yellow fruits and vegetables. Beta carotene is the most widely studied carotenoid. Evidence now strongly suggests that when taken as a separate supplement it can have harmful effects.
Lycopene. Lycopene is responsible for the red color in fruits and vegetables, including tomatoes, red grapes, watermelon, and pink grapefruit. It is also found in papayas and apricots. It does not convert to vitamin A but may have important cancer fighting properties and other health benefits.
The beneficial actions of most carotenes such as those tomatoes, corn, and carrots, appear to be enhanced by cooking them, especially in oil (preferably olive, canola, or another monounsaturated oil). (Note: Cooking can also destroy certain nutrients, such as vitamin C, in these vegetables.)

Xanthophylls contain oxygen and most are found in green vegetables, such as broccoli, cabbage, and kale. They are also in yellow fruits and vegetables. Xanthophylls include lutein and zeaxanthin, which are both stored in the retina of the eye. Neither converts to vitamin A. Both are powerful antioxidants and may be very important for healthy eyes. Unlike carotenes, cooking may reduce the antioxidant activity of some xanthophylls in foods, although probably not to any significant degree.

Phytochemicals

The word phytochemicals means plant chemicals. Hundreds of phytochemicals are being studied. Many are believed to have a major positive impact on human health. Some contribute to the bright and vivid colors found in fruits and vegetables. The results of studies on specific phytochemicals are not necessarily applicable to the vegetables or fruits that harbor small concentrations of these chemicals.

Nevertheless, it is obvious that vegetables and fruits are healthful, which is probably due to some balance of phytochemicals, carotenoids, vitamins, fibers, and minerals rather than any single substance.

The benefits of individual phytochemical supplements are largely unproven. Furthermore, they are not regulated and high concentrations of some may behave like drugs and can be toxic and possibly even contribute to cancer cell growth.

Polyphenols are important phytochemicals, and flavonoids (or catechins) are members of the polyphenol family that may have significant health benefits. Laboratory studies have shown that specific flavonoids suppress tumor growth, interfere with sexual hormones, prevent blood clots, and have anti-inflammatory properties. In general, flavonoids are found in celery, cranberries, onions, kale, dark chocolate, broccoli, apples, cherries, berries, tea, red wine or purple grape juice, parsley, soybeans, tomatoes, eggplant, and thyme. Most common berries contain flavonoids and are particularly rich in potent antioxidants.

Among the important flavonoids are resveratrol, quercetin, and catechin. Evidence suggests that resveratrol (found in red wine, grapes, olive oil) may be extremely potent. In laboratory studies, it increases cell survival and has been shown to increase the life span of worms and fruit flies. Catechins are the primary flavonoids in tea and may be responsible for its possible beneficial effects. Flavonoids in dark chocolate may also be health protective.

Isoflavones, commonly known as phytoestrogens, have actions that are similar to the female hormone estrogen. A high consumption of soy, which is primarily composed of isoflavones, may reduce symptoms resulting from estrogen depletion during menopause. In a recent study, supplementation with isoflavones decreased hot flashes by 57% and night sweats by 43%, but other research is less favorable.

Lignan is another phytoestrogen and is found in the fiber layers of whole-grains, berries, some seeds, some vegetables, and a few fruits.

Isothiocyanates and related substances, indoles, are also known as mustard oils and are responsible for the sharp taste in cruciferous (also called brassica) vegetables. Such vegetables include broccoli, cabbage, Brussels sprouts, cauliflower, collards, kale, kohlrabi, mustard greens, rutabaga, turnips, and bok choy. Isothiocyanates also stimulate enzymes that convert estrogen to a more benign form and may block steroid hormones that promote breast and prostate cancers. (Cruciferous vegetables are also high in fiber, vitamin C, and selenium.)

Monoterpenes have two important phytochemicals, perillyl alcohol and limonene. They block proteins that stimulate cell growth and reproduction and are being tested for actions against cancer. Limonene is found in the peels of citrus fruits.

Organosulfurs are part of the allium family of phytochemicals. Compounds, such as allicin, may have benefits on the immune system, assist the liver in rendering carcinogens harmless, and reduce production of cholesterol in the liver. These compounds are found in garlic, leeks, onions, chives, scallions, and shallots.

Capsaicin seems to reduce levels of substance P, a compound that contributes to inflammation and the delivery of pain impulses from the central nervous system. Research suggests that it may inhibit cancer-generating substances. It is found in hot red peppers.

Sterols, which include sitosterol, stigmasterol, campesterol, and squalene, are found in vegetable oils. Sitosterol is the most studied and appears to have cholesterol-lowering effects.

Beta-sitosterols may help improve urine flow and urinary symptoms in men with enlarged prostate glands (benign prostatic hyperplasia, or BPH). A recent review study of five randomized trials (519 men) found that urinary flow and other urinary symptoms improved in men who took the herbal remedy from 4 - 26 weeks. The study’s authors cautioned that while beta-sitosterols show effectiveness in the short term, their long-term effectiveness, ability to prevent complications from BPH, and safety are not known. More research is necessary. Beta-sitosterols come from South African star grass, Hypoxis rooperi, or species of Pinus and Picea.

Healthy Foods

Evidence increasingly suggests that a varied diet, not individual food chemicals, is essential for basic health and a longer life. Such diets are rich in fresh fruits and vegetables and whole grains, and low in saturated fats.


Foods	Phytochemicals and Carotenoids	Vitamins and other valuable food components	Benefits
Apples	Flavonoids		May have activity against certain cancers (lung). Also may help maintain healthy cholesterol. May protect against asthma.
Beans	Flavonoids	Folate, iron, potassium, and zinc	Some experts believe beans are the perfect food.
Berries, all kinds of dark colored	Ellegic Acid	Vitamin C, minerals	The anthocyanins in berries such as bilberries, blueberries, cranberries, elderberries, and others, have numerous healthful properties including anti-cancer and antioxidant effects. Bilberry (Vaccinium myrtillis) is widely used to prevent macular degeneration. Blueberries may protect the aging brain. (In one study blueberries were most effective.)
Broccoli (also kale, Brussels sprouts, cauliflower)	Flavonoids, isothiocyanates, lutein, beta and alpha carotene. Note: Young sprouts of broccoli and cauliflower contain much higher levels of isothiocyanates than their mature forms.	Vitamin C, folate, fiber, and selenium	Anticancer properties. Protective against heart disease and stroke.
Carrots and other bright yellow vegetables	Lutein, beta carotene and other provitamin A carotenoids	Vitamin A (converted from carotenoids), vitamin C	Protects eyes, lungs. (Cooking carrots may increase the potency of food nutrients.)
Chocolate, dark. Note: Milk chocolate does not have benefits.	Flavonoids		Heart protective (may improve lipids and help prevent blood clotting. May have protective properties against lung cancer (not other cancers).
Eggs	Lutein	Many B vitamins, vitamin A, vitamin D	Although egg yolks are high in cholesterol, very little of it has a negative effect on people with normal levels. And the health benefits of eggs are now known to be very high. (People with diabetes or those with high cholesterol should restrict eggs, however.)
Fish, oily (mackerel, salmon, sardines)		Vitamin B3, B12. Essential fatty acids, selenium	Heart and brain protective.
Garlic	Allium (organosulfurs)		Possibly protective against certain cancers, heart diseases, and infection. Heating garlic can reduce benefits. Allowing crushed fresh garlic to stand 10 minutes before heating, however, may preserve beneficial chemicals while cooking.
Ginger	Zingiberaceae		Cancer fighting properties.
Grains (whole)	Lignans (phytoestrogens)	Vitamin B, Selenium (important antioxidant mineral), fiber, folate	May help reduce the ability of cancer cells to invade health tissue.
Grapes, including purple grape juice, and red wine	Flavonoids, (resveratrol, quercetin and catechin)		Fight heart disease and cancer. May help lower the risk for asthma.
Nuts		Vitamin E, vitamin B1, essential fatty acids, folate	Protects the heart and may help prevent stroke.
Onions	Flavonoids, allium (organosulfurs)		May have activity against certain cancers (lung).
Oranges	Monoterpenes	Vitamin C, folate, potassium.	Many health benefits. Increases HDL levels.
Potatoes (Sweet)		Vitamin C, vitamin E, vitamin A	Many health benefits.
Soy. The best products are tofu, soy milk, or whole soy protein.	Isoflavones (phytoestrogens), flavonoids, phytosterol, phytate, saponins.		May have effects similar to estrogen, including maintaining bone and benefiting the heart in women. May also be protective against prostate cancer and possibly other cancers. More studies are needed. Effects on breast cancer are uncertain. (Note: Soy may have different effects in men than in women. Of some concern is one study reporting more mental decline in men who consume greater amounts of tofu.)
Spinach and other dark green leafy vegetables	Zeaxanthin, Beta carotene	Vitamin C, folate, vitamin A (converted from carotenoids)	Protects lungs and brain.
Tea (Both black and green tea are beneficial. Best results associated with green tea.)	Flavonoids (primarily catechins)		Cancer fighting properties, particularly in green tea, which may be especially beneficial for smokers. Both black and green tea may protect against heart disease and stroke, although studies are mixed. Tea drinking also may help with weight control and help prevent osteoporosis.
Tomatoes	Lycopene, Flavonoids	Vitamin C, biotin, minerals	Studies link to reductions in prostate and other cancers. Infection fighters.
Note on Organic versus Inorganic Products. There is some evidence that organic produce has higher levels of antioxidants and that some agricultural chemicals may destroy flavonoids. Nevertheless, organic produce is expensive, and fruits and vegetables, no matter how they are grown, are still filled with healthful nutrients.

Dietary Health Benefits

The benefits of any dietary factors are very difficult to prove, and, to date, there is little evidence that most dietary supplements protect against major diseases in otherwise healthy people with normal eating habits. An exception is lutein, which is known to reduce the risk of macular degeneration. However, a diet naturally high in vitamins and minerals can be the best defense against many diseases. Fresh fruits and vegetables and whole grains are the primary sources of vitamins, carotenoids, and vitamins, as well as of fiber and important minerals.

Description of Oxygen-Free Radicals (Oxidants). Currently, the most important benefit claimed for vitamins A, C, E, and many of the carotenoids and phytochemicals is their role as antioxidants, which are scavengers of particles known as oxygen-free radicals (also sometimes called oxidants). These chemically active particles are by-products of many of the body's normal chemical processes. Their numbers are increased by environmental assaults, such as smoking, chemicals, toxins, and stress. In higher levels, oxidants can be very harmful in the following way:

They can damage cell membranes and interact with genetic material, possibly contributing to the development of a number of disorders including cancer, heart disease, cataracts, and even the aging process itself.
Oxygen-free radicals can also enhance the dangerous properties of low-density lipoprotein (LDL) cholesterol, a major player in the development of atherosclerosis.

Description of Antioxidants and Warnings on High-Dose Supplements. Antioxidant vitamins (A, C, and E), carotenoids, and many phytochemicals can neutralize free radicals. Unfortunately, although it is clear that vitamins are required to prevent deficiency diseases, high doses of vitamin C, vitamin E, and beta carotene supplements may also have pro-oxidant effects, which can be harmful in patients with cancer. In these people, high doses of antioxidant vitamins may actually protect cancer cells just as they do healthy cells.

The strongest evidence on negative effects to date comes from studies reporting an increase in lung cancer and overall mortality rates among smokers who took beta carotene supplements. In determining reasons for this disturbing effect, one animal study suggested that beta carotene increased enzymes in the lungs that actually promote cancerous changes. One study also reported a higher risk for cancer in male smokers who took multivitamins plus A, C, or E.

Some evidence also indicates that high doses of vitamin C may speed up atherosclerosis, or hardening of the arteries. In one study, women with heart disease who took antioxidant vitamins had a higher risk for heart attack or death than those who didn't take one.

Another study also reported a higher incidence and greater severity of respiratory infections in older adults who took 200 mg of vitamin E daily. Some researchers speculate that certain immune factors generate oxidants to fight bacteria. This antioxidant vitamin, then, may block that action. Research published in 2005 suggests that those who take large amounts of vitamin E (1,500 IU/day) may slightly increase their risk for heart failure and death, but this evidence is not considered conclusive. Further study is necessary.

Vitamins and Heart Protection.

Antioxidant Vitamins A, C, and E. Deficiencies in vitamins A, C, E, and beta carotene have been linked to heart disease. All of these nutrients have antioxidant effects and other properties that should benefit the heart. A study in patients with heart failure has shown that vitamin C can work with dobutamine, a powerful intravenous medication, to strengthen the heart’s ability to contract following a heart attack. In fact, a 2005 study has found that taking high doses of vitamin E is associated with an increased risk of heart failure. In 2007, the Women’s Antioxidant Cardiovascular Study failed to find that vitamins C, E, and beta carotene could reduce the risk of heart attack, stroke, need for revascularization, or cardiovascular death in women. According to the U.S. Preventive Service Task Force, evidence is insufficient to confirm or refute the benefits of supplements of any of these vitamins in protecting against heart disease.
Folate and B12 Vitamins. Deficiencies in the B vitamins folate (known also as folic acid) and B12 have been associated with elevated blood levels of homocysteine, an amino acid that has been associated with a higher risk for heart disease, stroke, and heart failure. One study, reported lower failure rates after heart surgery in patients who took folic acid and vitamins B12 and B6. And a major 2002 study suggested that lowering homocysteine levels with folic acid would reduce the risk for heart disease by 16% and stroke by 24%. However, a 2007 trial in adults with stable coronary artery disease found that lowering homocysteine levels 33% with B vitamins and folic acid had no effect on arterial inflammation, meaning that lower levels were unlikely to offer protection against heart attack or stroke. More evidence is needed to determine whether homocysteine plays a causal role in cardiovascular disease and whether the B vitamins are protective. Folate improves blood flow through the arteries, which may be important for the heart, regardless of its effect on homocysteine. Although people with high levels of homocysteine are prone to damaging blood clots in their arteries and veins, a 2007 study found that lowering homocysteine with folic acid and other B vitamins does not reduce the incidence of blood clots in the peripheral veins (deep venous thrombosis).
Niacin. Niacin (vitamin B3) is used for lowering unhealthy cholesterol levels. Although vitamin B3 is available over the counter, it can have significant side effects. A physician should prescribe niacin in order to ensure its safety and effectiveness. [See In-Depth Report #23, Cholesterol.]

Carotenoids and Heart Protection. Studies have reported that a diet high in fruits and vegetables containing beta carotene, lycopene, and other carotenoids may reduce the risk of heart attack. A small Finish study found that a diet high in tomatoes reduced total cholesterol and LDL ("bad") cholesterol. Diets low in lycopene (particularly from tomatoes) were associated with a significantly higher risk of heart disease and stroke.

Atherosclerosis is a disease of the arteries in which fatty material is deposited in the vessel wall, resulting in narrowing and eventual impairment of blood flow. Severely restricted blood flow in the arteries to the heart muscle leads to symptoms such as chest pain. Atherosclerosis shows no symptoms until a complication occurs.

Phytochemicals and Heart Protection. Several phytochemicals are associated with heart protection.

Flavonoids. Certain flavonoids, found in both black and green tea, dark chocolate, onions, red wine or red grape juice, and apples, appear to be strongly heart protective. In one study, people who consumed the most flavonoids in foods had a 20% lower risk for heart disease than those with low consumption. Flavonoids may protect against damage done by cholesterol and help prevent blood clots. A number of studies have now reported heart protection from the flavonoid catechin, which is found in both black and green tea. The flavonoid resveratrol, which is found in grape skin, appears to be responsible for the well-known heart protective effects in red wine and purple grape juice.
Organosulfurs. Organosulfurs found in onions and garlic have been under investigation for possible beneficial effects on cholesterol levels. One study reported an association between taking garlic capsules and significantly lower cholesterol-build up in the arteries of older women but not in older men. In the study, daily garlic supplements dramatically reduced the build-up of newly formed plaque in the arteries, while having much less effect on older, harder plaque deposits. Garlic supplements for cardiovascular disease may be most beneficial when used during earlier years among men and later years among women.
Isoflavones. Soy protein is the most studied source of isoflavones (known as phytoestrogens, or plant estrogens). Not all studies are consistent, but the majority has shown an improvement in at least one of the cholesterol components in people who consumed at least 25 grams of soy protein. A 2007 meta-analysis of all soy protein studies performed from 1990 - 2006 found that soy protein significantly decreased total cholesterol and LDL cholesterol, but had no effect on HDL or triglycerides. The effect was particularly evident in people with hypercholesterolemia. A 2007 study found that 12 weeks of soy supplement lowered total cholesterol and LDL levels in both Caucasian and African-American postmenopausal women. Soy may also reduce other heart risk factors, at least in certain populations. For example, in one 2002 study, soy was beneficial for controlling blood sugar and lowering LDL in postmenopausal women with type 2 diabetes. In a 2007 study of overweight men and postmenopausal women, soy protein reduced blood pressure and arterial stiffness. In another study, soy protein was associated with lower systolic blood pressure in men. The best sources are soy products (tofu, soy milk) or whole soy protein. Powdered soy protein that contains at least 60 mg of isoflavones may provide similar benefits.
Sterols. The plant sterols, including sitosterol, are also proving to be potent cholesterol fighters by blocking the absorption of cholesterol in the intestine. Sitostanol, a derivative of sitosterol, is being used in new margarine products to lower cholesterol levels. Sterols and stanols are now found in breads, cereals, yogurt, and fruit juices.

A healthy diet rich in fruits and vegetables and low in salt and saturated fats may significantly lower the risk for a first stroke, perhaps by helping to protect against high blood pressure -- a major risk factor for stroke.

Vitamins and Stroke Protection. The effects of antioxidant vitamins and carotenoids on stroke, dementia, or both are being studied. Studies are conflicting, however. A 2007 study of 8,171 women with cardiovascular disease reported that vitamins C, E, and beta carotene offered no protection against heart attack and stroke.

The B vitamin folate (usually in the form of folic acid) may protect against stroke. However, exactly which people benefit from this therapy has yet to be determined. Studies have suggested that people who have higher blood levels of folate have a lower than average risk for stroke. Its primary benefit in this case appears to be to reduce levels of homocysteine, an amino acid that has been strongly linked to an increased risk of coronary artery disease, stroke, and Alzheimer's disease. A 2007 meta-analysis of 8 trials found that folate supplements decreased homocysteine 20% and lowered stroke risk 18%. Interestingly, lowering homocysteine with folic acid and B vitamins had no effect on heart attack, strokes, amputations, need for dialysis, or death in patients with chronic or end-stage kidney disease.

Carotenoids and Stroke Protection. Some, but not all, studies have reported a lower risk of stroke from carotenoids, including beta carotene and lycopene.

Many fresh fruits and vegetables contain chemicals that may fight many cancers, including lung, breast, colon, and prostate cancers. Examples of important cancer fighting foods include the following:

Cruciferous vegetables (such as cabbage, Brussels sprouts, and broccoli)
Tomatoes (which contain lycopene)
Carrots (which contain alpha carotene)

Some evidence suggests that antioxidants may enhance the anticancer effects of chemotherapy. In multiple studies, patients who maintained their antioxidant levels were better able to withstand the high stress caused by chemotherapy or radiation therapy compared to those with low antioxidant levels. Antioxidant nutrients that may help reduce the side effects of chemotherapy include vitamins E and C, beta carotene, genistein and daidzein (isoflavones found in soy), and quercetin (found in red wine an purple grape juice).

Any protective effects of vitamins or specific phytochemical against cancer, however, appear to depend on the cooperative effort among them. Individual supplements of any vitamin or food chemical have not as yet shown any benefits.

Additionally, certain supplements may actually encourage tumor growth, particularly when taken in large amounts. Two 2007 studies found a connection between folate supplements and colorectal cancer. In one study, which was designed to evaluate the benefits of folic acid in patients who had previous colorectal adenomas (precancerous polyps), the researchers instead found that folic acid was associated with a higher risk of having 3 or more adenomas and noncolorectal cancers. In another study, it was noted that the downward trend in colorectal cancer diagnoses abruptly started to rise in 1996 when mandatory folate enrichment of grains within the U.S. and Canada began. Rates continue to exceed pre-1996 levels. Additionally, a large 2007 National Cancer Institute/AARP study found an increased risk of advanced and fatal prostate cancer in men who took more than 7 multivitamins a week, but no association between multivitamin use and localized prostate cancer.

High consumption of cruciferous vegetables (at least once per week) was associated with lower risk of kidney cancer, and low consumption (less than once per month) of cruciferous vegetables was associated with higher risk of kidney cancer in a multinational 2007 European study. Cruciferous vegetables also appear to offer protection against head and neck cancer resulting from chemical toxins found in cigarettes and alcohol, for example.

Vitamins and Cancer Protection. Because many cancers are thought to be initiated by the effects of oxygen-free radicals on DNA, the antioxidants A, C, and E and beta carotene have been intensively studied. A major study found that men who took selenium for 6 or 7 years reduced their risk of prostate cancer by 52%. Nevertheless, most individual supplements have not been proven to protect against cancer, and high doses may be dangerous.

A 2007 review of the diets of men exposed to asbestos found a decreased risk of prostate cancer associated with increasing intakes of vitamin C-rich vegetables, but not fruits and vegetables high in vitamin A. The chemopreventive role of silymarin (Silybum marianum), found in milk thistle extract, has been extensively studied and has shown anticancer efficacy against various cancers, especially prostate and skin, by inhibiting UVB radiation.

A review of 13 cancer registries found 416,134 cases of skin cancer and 3,776,501 cases of non-skin cancer as a first cancer. Rates from cancer registries in sunny countries (such as Australia and Spain) and less sunny countries (such as Canada and Iceland) were compared. The researchers concluded that vitamin D production in the skin decreases the risk of several solid cancers, especially stomach, colorectal, liver and gallbladder, pancreas, lung, female breast, prostate, bladder, and kidney cancers. The apparently protective effect of sun exposure against second primary cancer is more pronounced after non-melanoma skin cancers than melanoma.

Consumption of aflatoxins, a common fungus-related toxin infecting cereal grains, oil seeds, spices, tree nuts, and the milk of animals fed contaminated feed, is known to cause hepatocellular carcinoma, a deadly form of liver cancer. Rodent studies have shown that phenolic antioxidants, dithiolethiones, isothiocyanates, and triterpenoids may act as chemopreventive agents, dispersing aflatoxins and protecting against hepatocellular carcinoma. Human trials are planned. A similar study found that several isothiocyanates, diallyl sulfide, and polyphenolic compounds can prevent esophageal dysplasia from progressing to squamous cell carcinoma.

A review of all articles on vitamins and cancer published through February 2007 found that multivitamin/mineral supplement use may prevent cancer in individuals with poor or suboptimal nutritional status. One trial on poorly nourished Chinese showed supplementation with combined Beta-carotene, vitamin E and selenium reduced gastric cancer incidence and mortality, and overall cancer mortality. In a French trial, combined vitamin C, vitamin E, beta-carotene, selenium, and zinc reduced cancer risk in men but not in women. With few exceptions, neither beta-carotene nor vitamin E had benefits for preventing cancer. Beta-carotene supplementation increased lung cancer risk in smokers and persons exposed to asbestos.

A 2007 study of nearly 82,000 men and women in Sweden found that high intake of methionine was associated with reduced risk of pancreatic cancer. The same relationship was not seen with vitamin B6 or folate.

Vitamin A, C, and E. Although some studies have reported an association between low blood levels of these antioxidant vitamins and a higher risk for cancer, supplements of vitamins A, C, and E appear to have few advantages in most cases. And there are some studies finding higher cancer risks with high intakes of antioxidants. For example, a 2003 study reported a higher risk in melanoma in people with vitamin-C rich diets. Another study also reported a higher risk for cancer in male smokers who took multivitamins plus A, C, or E. (Vitamin E may be protective against bladder cancer and ovarian cancer.)
Vitamin D. Some studies have suggested that certain vitamin D compounds may inhibit certain cancer cells, specifically prostate cancer, from proliferating. More research is needed. In 2007, the National Cancer Institute confirmed that ultraviolet (UV) radiation exposure may reduce the risk of developing non-Hodgkin lymphoma (NHL), but only in patients with certain variations in the D vitamin receptor gene. A second 2007 study found that variations in this gene increase the risk of diffuse large B-cell lymphoma. A 2007 prospective analysis of 31,500 women in the Women’s Health Study evaluated calcium and vitamin D intake. The researchers found a moderately lower risk of premenopausal, but not postmenopausal, breast cancer with higher intakes of total calcium and vitamin D. A 2007 review of breast cancer cases reported in Ontario, Canada, found reduced breast cancer risks were associated with increasing sun exposure in women ages 10 - 19, less evidence for associations in women ages 20 - 29, and no evidence for ages 45 - 54. Researchers concluded that sun exposure earlier in life, particularly during breast development, may be key in the connection between vitamin D exposure and breast cancer risk.
Folic acid and B12. These B vitamins convert the amino acid homocysteine to methionine, a substance that helps prevent cells from becoming malignant. Folic acid may provide some protection against cervical and colon cancer. One small study showed a reduction of lung cancer cells in smokers taking folic acid and vitamin B12, but the study was very small, of short duration, and other factors might have biased the results. Still another study reported that folic acid may reduce the risk for breast cancer among women who regularly drink alcohol. (In the study, folic acid had no other effect on breast cancer.)

In 2006, a study for the National Institutes of Health reviewed randomized trials evaluating the effectiveness and safety of multivitamin and mineral supplements in preventing cancer and chronic disease. The studies had mixed results, and some supplements reduced cancer rates in certain populations. However, the reviewers concluded that current evidence is not sufficient to determine whether multivitamin and mineral supplements may prevent cancer and chronic disease.

Carotenoids and Cancer Protection. A number of studies have reported that fruits and vegetables rich in carotenoids are associated with protection against many cancers. Lycopene, found in tomatoes, may have particular value in protection against prostate, colon, lung, and bladder cancer. A 2005 study found that in one out of four men with genetic variations that cause them to be more sensitive to oxidative stress, supplementation with selenium, vitamin E, and lycopene significantly reduces the risk of prostate cancer. Individual supplements, however, do not offer any advantage. In fact, evidence now strongly suggests that beta carotene supplements increase the risk for lung cancer in smokers and people exposed to asbestos

Phytochemicals and Cancer Protection. The following phytochemicals appear to have cancer-protecting properties.

Isothiocyanates. Isothiocyanates and sulforaphane, found in cruciferous vegetables, may block the effects of carcinogens and suppress tumor growth. In one study, for example, women with the highest consumption of cruciferous vegetables had a 24% lower risk of breast cancer than women with the lowest consumption.
Isoflavones. Isoflavones, found in soy beans and flax seed, behave like estrogen in some ways and not in others. Researchers are very interested, then, in their effects on hormone-related cancers, including breast and prostate cancers. Much research has focused on soy. In general, a number of Asian studies have reported an association between a higher intake of soy and a lower incidence of reproductive and breast cancers. The effects of phytoestrogens, however, in all women are far from settled. Some evidence suggests the genistein in soy may have properties that are protective against lung cancer. Nonfermented soy products (tofu, soy milk) also may protect against stomach cancer, while fermented soy products (miso, soy paste) appears to increase the risk.
Organosulfurs. The organosulfur compounds found in the onion and garlic family may have very potent properties in suppressing or blocking carcinogenic substances. A 2007 study found that synthetic organosulfur compounds act as selective inhibitors of growth in breast cancer cells. Studies indicate that people who regularly consume fresh or cooked garlic have about half the risk of developing stomach cancer and two thirds the risk of colorectal cancer as people who eat little or no garlic. One possible explanation for garlic's anti-cancer effect in the stomach is its antibacterial action against H. pylori, which can promote stomach cancer. Taking garlic supplements, however, did not offer these benefits.

It should be noted that studies on the health benefits of vitamins and minerals have some important limitations. Some are held to rigorous standards, while others are not. In most cases, the results of existing research are complex, as they can easily be complicated by factors such as diet, exercise, the presence of healthy or unhealthy lifestyle behaviors, environmental factors, and more.


Disease or Condition	Vitamins	Carotenoids, Phytochemicals, and Healthy Foods
Alzheimer's Disease	Vitamin E. Some reports, including a large 2002 population study, have suggested that vitamin E intake, from food or supplements, may protect against mental decline. (One study suggested that the vitamin protected only those who carried the apoE4 gene. No strong evidence to date has found any protection from antioxidant supplements.) Some studies performed since 2002 challenge this finding, while others agree with it. B Vitamins. Some studies suggest that deficiencies of the B vitamins B6, B12, and folate may be a risk factor for Alzheimer' diseases, possibly because deficiencies elevate homocysteine levels, which some research now associated with a higher risk for Alzheimer's disease. Of these, folates may offer the best protection. In 2007, researchers at Tufts-New England Medical Center reviewed all human studies on folate, vitamin B-6, vitamin B-12, and cognitive function in the elderly conducted between 1966 and November 2006. Six of 10 folate studies reported a significant association between low baseline blood folate concentrations and poor cognitive test performance; 4 of 9 folate studies found associations between low blood folate concentrations and increased prevalence of Alzheimer's disease. No association between vitamin B-6 and vitamin B-12 blood concentrations and cognitive-test performance or Alzheimer's disease was seen, and B-vitamin dietary intake was not associated with cognitive function. Although the majority of studies indicated that low blood folate concentrations predicted poorer cognitive function, data are not solid, due to variations in the way the studies were conducted and lack of agreement on what constitutes a low B-vitamin status.	According to several studies, eating plenty of darkly colored fruits and vegetables may slow brain aging. The estrogen-like properties in isoflavones are of interest in the study of Alzheimer's disease. Animal studies suggest that soy might be protective against AD, particularly in postmenopausal women. Of some concern, however, were one population and a few animal studies suggesting that soy intake may pose a risk for greater mental decline among older men. More research is needed to confirm the effects of soy on the aging brain and to determine if there are gender differences.
Infectious Disease	Studies are mixed whether vitamin supplements protect against upper respiratory infections. Large doses of vitamin C, for example, may help reduce the duration of a cold, but they do not appear to protect against one in the first place, even after exposure to a cold virus. Two studies in 2002 on multivitamins reported opposite results, with one finding fewer infections and one finding no difference. It is possible that vitamin C or multivitamin supplements may be helpful in specific people, such those who are vitamin deficient or have medical problems that impair their immune systems. A review of all studies on vitamin C and pneumonia prevention found only 1 placebo-controlled, randomized trial conducted in an English boarding school during World War II. The trial found a statistically significant (80% or greater) reduction in pneumonia incidence among boys consuming vitamin C. Two less-well-constructed trials arrived at the same conclusion. Therapeutic trials were even scarcer. Only one randomized, double-blind, placebo-controlled study of vitamin C for treatment of pneumonia was found. In this trial, elderly patients given vitamin C had lower mortality and respiratory symptom scores. However, the benefits were restricted to the sickest patients. One other trial of adults in the former Soviet Union found a dose-dependent reduction in the time to recover with two vitamin C doses. One 2007 study on vitamin D found that a single dose by mouth of this vitamin might prevent healthy individuals from activating the bacterium that causes tuberculosis in patients who harbor the infection. Studies on vitamin E specifically have been mixed. A 2002 study, in fact, reported a higher incidence and greater severity of respiratory infections in older adults who took 200 mg of vitamin E daily. However, a 2004 clinical trial conducted among elderly nursing home residents found that daily supplementation with 200 IU of vitamin E did provide protection from upper respiratory infections, especially the common cold. At present, there is not enough evidence to recommend vitamin E for infection prevention. Diarrhea is a worldwide problem, particularly in developing countries and those with poor sanitation. Taking supplements with B-complex vitamins, vitamin C, vitamin E, and selenium may reduce the risk of diarrhea, depending upon the organism that causes the disease. Meanwhile, iron supplements appear to increase the risk of infection from organisms that cause diarrhea. Vitamin A has not been shown to prevent diarrhea. Urinary tract infections (UTIs) may affect as many as 25% of pregnant women. A 2007 study found that women who took vitamin C (100 mg) for 3 months had significantly fewer UTIs than women who did not take vitamin C supplements. Rotavirus is a common cause of acute gastric pain in children under age 5. A 2007 study showed that the high amount of isoflavones found in soy-based infant formula can help prevent rotavirus infection.	Lycopene, found in tomatoes, appears to have properties that protect infection-fighting white blood cells. Saponins extracted from ginseng and allicin (found in garlic) have properties that boost the immune system. Both ginseng and garlic have long been traditionally used for their health benefits.
Asthma	Vitamin C from diet has been associated with lower risk for asthma. In one study, some people with exercise-induced asthma benefited from taking vitamin C one hour before strenuous physical activity. In a 2007 study, taking 1,500 mg supplements of vitamin C for 2 weeks helped prevent exercise-induced airway narrowing in patients with asthma.	Flavonoids found in apples and red wine may help lower the risk for asthma. Some evidence indicates that a low dietary intake of antioxidant nutrients could increase the risk for lung damage. Such nutrients should be obtained from fresh, deep green and yellow-orange fruits and vegetables. A 2007 study found low blood lycopene levels in people with asthma. Increasing lycopene- and vitamin A-rich foods may help raise lycopene levels.
Eye Disorder	Cataracts and Macular Degeneration. Oxygen-free radicals play a role in cataract formation and age related macular degeneration, the most common cause of irreversible blindness in the elderly. Bilberry (Vaccinium myrtillis), which contains powerful anthocyanins, is widely used to prevent macular degeneration. Low levels of vitamin C in the lens of the eye have been particularly strong predictors of cataracts. People with cataracts are frequently deficient in vitamin A, the carotenes, lutein, and zeaxanthin. Studies on protection against cataracts using antioxidant supplements have been mixed, including two identically conducted studies that reported opposite results. Vitamin C currently has the strongest evidence for protection, but even with this antioxidant studies are not consistent. A combination of zinc and antioxidants, including vitamin C and E, may slow the progression of macular degeneration. (Vitamin E alone does not appear to be protective.) Glaucoma. Although no evidence exists that antioxidants will prevent glaucoma, some studies reported an association between vitamin E and improved visual fields in patients with glaucoma.	Several studies report that the consumption of antioxidant-rich foods is associated with a decreased risk for cataracts. Carotenoids, especially lutein, lycopene, and zeaxanthin, are especially eye-protective and may help prevent cataracts and macular degeneration. The National Eye Institute in 2007 suggested that people with intermediate- or advanced macular degeneration in one eye may want to take a vitamin formula shown to reduce the risk of macular degeneration in the other eye by 25%. The formula contains vitamin C, vitamin E, beta-carotene, and zinc. They also suggest that a diet high in lutein and zeaxanthin may help reduce the risk of advanced age-related macular degeneration. Several studies report that the consumption of antioxidant-rich foods is associated with a decreased risk for cataracts. Carotenoids, especially lutein lycopene, and zeaxanthin are especially eye-protective and may help prevent cataracts and macular degeneration.
Skin Disorders and Wrinkles	Topical vitamin A (retinol) has been shown to improve fine wrinkles due to aging, by increasing glycosaminoglycan, which retains water, and increasing collagen production. One small study found that taking a combination of vitamins oral C and E supplements may help reduce sunburn reactions, although the protection is much less than from sunscreens. Taking the vitamins singly did not have any effect. In fact, a 2002 study reported that oral vitamin C had no effect on sunburn reaction. Of concern, in the same study some natural antioxidants in the body were reduced in people who took the vitamin. Also of concern are studies reporting no benefits and possibly harm from topical vitamin C in the form of ascorbyl palmitate, which is soluble in fat. One study reported that older adults had fewer wrinkles if they ate whole grains, fresh fruits and vegetables, and the use of healthy oils (such as olive oil). Diet played a role in improving skin regardless of whether the people in the study smoked or lived in sunny countries.	The following foods and phytochemicals may be especially skin protective: Both green tea and ginger appear to have properties that may provide some protection against skin cancer. Green tea skin care products are now available. The substance silymarin, found in the milk thistle family (which includes artichokes), may inhibit UVB-promoted cancers in animals. In one interesting study, eating garlic protected animals very effectively against UVB damage by interfering with urocanic acid in the skin. Whether these results may apply to humans (and what quantities of garlic might be beneficial) is still unknown.
Osteoporosis	Vitamin D. Vitamin D is the essential companion to calcium in maintaining strong bones. Supplements may be needed for people who have poor exposure to sunlight. It should be noted that diet supplies most people's need and high amounts of vitamin D can be toxic. Of interest: Taking vitamin D supplements does not prevent bone loss in post-menopausal African American women, according to research published in 2005. Further study will be needed to determine whether vitamin D prevents bone loss in women from other ethnic groups. Vitamin K. Studies suggest that vitamin K has properties that protect bone and prevent fracture. Vitamin K2 (menatetrenone), a form of vitamin K, is proving to prevent fractures in people with osteoporosis. Vitamin K affects blood clotting, and supplements are not recommended without specific physician instruction. Vitamin B12. One study reported that in people with osteoporosis and pernicious anemia, taking vitamin B12 (which is used to treat the anemia) also increased bone density. Vitamin C and E. There has been some indication of a positive association between vitamin C and E intake and bone density, although evidence proving actual benefits is weak. Note on Vitamin A. High amounts of dietary vitamin A reduces bone density and may even increase the risk for fracture in both postmenopausal women and men. (A form of vitamin A, retinoic acid, has been found to stimulate bone break down.) Beta carotene does not appear to increase risk. Studies suggest that diets rich in fresh fruits and vegetables (which include those high in potassium and magnesium) reduce elimination of calcium from the body and help preserve bones.	Studies suggest that diets rich in fresh fruits and vegetables (which include those high in potassium and magnesium) reduce elimination of calcium from the body and help preserve bones. Studies are suggesting that isoflavones-rich soy products may actually improve bone density in postmenopausal women. A 2007 study of postmenopausal women in Italy found that 24 months of treatment with genistein plus calcium and vitamin D increased bone density, while women who took calcium and D alone lost bone density. Flavonoids and other compounds in tea may protect the bones.
Menstrual Disorders	Vitamin B6. Limited clinical evidence suggests that vitamin B6 may be beneficial in reducing premenstrual symptoms, including depression. Typically, women take 100 mg per day, although one study suggested that a lower dose (50 mg) may have the same effect. Other preliminary research indicates that women who receive the equivalent of 1,200 mg of calcium and 400 IU of vitamin D per day (through food or supplements) have a significantly lower incidence of premenstrual symptoms than women who did not. Vitamin B1. One study reported relief from menstrual pain using vitamin B1 (thiamin). Vitamin E. Several randomized controlled trials have shown that vitamin E significantly improves both physical and emotional premenstrual symptoms. One study reported that high doses of vitamin E helped reduce menstrual cramps. The doses were much higher than those recommended and could possibly increase the risk for bleeding. Although anecdotal evidence reports that vitamin E helps reduce the frequency of hot flashes for menopausal women, there is no clinical evidence to support this claim.

Resources

http://fnic.nal.usda.gov -- The Food and Nutrition Information Center
http://dietary-supplements.info.nih.gov -- Office of Dietary Supplements, National Institutes of Health
www.ars.usda.gov/ba/bhnrc/ndl -- Nutrient Data Laboratory
www.fda.gov -- Food and Drug Administration
www.eatright.org -- The American Dietetic Association
www.acsh.org -- American Council on Science and Health
www.aicr.org -- American Institute for Cancer Research
www.nutritiondata.com -- Information on vitamins and nutrients in foods
www.consumerlab.com -- Independent testing of nutritional supplements' contents and quality
www.usp.org -- US Pharmacopeia
www.herbs.org -- Herb Research Foundation

References

Age-Related Eye Disease Study Research Group, SanGiovanni JP, Chew EY, Clemons TE, Ferris FL 3rd, Gensler G, Lindblad AS, Milton RC, Seddon JM, Sperduto RD. The relationship of dietary carotenoid and vitamin A, E, and C intake with age-related macular degeneration in a case-control study: AREDS Report No. 22. Arch Ophthalmol. 2007;125(9):1225-1232.

Ambrosini GL, de Klerk NH, Fritschi L, Mackerras D, Musk B. Fruit, vegetable, vitamin A intakes, and prostate cancer risk. Prostate Cancer Prostatic Dis. 2007 May 22; [Epub ahead of print]

Aubertin-Leheudre M, Lord C, Khalil A, Dionne IJ. Six months of isoflavone supplement increases fat-free mass in obese-sarcopenic postmenopausal women: a randomized double-blind controlled trial. Eur J Clin Nutr. 2007 Feb 21; [Epub ahead of print]

Bermudez Y, Ahmadi S, Lowell NE, Kruk PA. Vitamin E suppresses telomerase activity in ovarian cancer cells. Cancer Detect Prev. 2007;31(2):119-28. Epub 2007 Feb 28.

Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM. Maternal vitamin d deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab. 2007 ;92(9):3517-22. Epub 2007 May 29.

Clements RH, Katasani VG, Palepu R, Leeth RR, Leath TD, Roy BP, Vickers SM. Incidence of vitamin deficiency after laparoscopic Roux-en-Y gastric bypass in a university hospital setting. Am Surg. 2006;72(12):1196-202.

Coull DB, Tait RC, Anderson JH, McKee RF, Finlay IG. Vitamin B12 deficiency following restorative proctocolectomy. Colorectal Dis. 2007;9(6):562-566.

Dietary Guidelines for Americans 2005. Dept of Health and Human Services, US Dept of Agriculture. Accessed 10/3/2007.

Fischer Walker CL, Black RE. Micronutrients and diarrheal disease. Clin Infect Dis. 2007;45 Suppl 1:S73-S77.

Glynn RJ, Ridker PM, Goldhaber SZ, Zee RY, Buring JE. Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism: report from the Women's Health Study. Circulation. 2007;116(13):1497-503.

Headstrom PD, Rulyak SJ, Lee SD. Prevalence of and risk factors for vitamin B(12) deficiency in patients with Crohn's disease. Inflamm Bowel Dis. 2007 Sep 20; [Epub ahead of print]

Inderjeeth CA, Glennon D, Petta A, Soderstrom J, Boyatzis I, Tapper J.Vitamin D and muscle strength in patients with previous fractures. N Z Med J. 2007;120(1262):U2730.

Ishihara J, Otani T, Inoue M, Iwasaki M, Sasazuki S, Tsugane S; Japan Public Health Center-based Prospective Study Group. Low intake of vitamin B-6 is associated with increased risk of colorectal cancer in Japanese men. J Nutr. 2007;137(7):1808-1814.

J.G. Ray, C. Kearon, Q. Yi, P. Sheridan, and E. Lonn, for the Heart Outcomes Prevention Evaluation 2 (HOPE-2) Investigators. Randomized Trial of Homocysteine-Lowering Therapy and Risk for Venous Thromboembolism. Ann Intern Med. 2007;146(11):761-767.

Kitchin B, Morgan SL. Not just calcium and vitamin D: other nutritional considerations in osteoporosis. Curr Rheumatol Rep. 2007;9(1):85-92.

Kune G, Watson L. Colorectal cancer protective effects and the dietary micronutrients folate, methionine, vitamins B6, B12, C, E, selenium, and lycopene. Nutr Cancer. 2006;56(1):11-21.

Lim MR, Huang RC, Wu A, Girardi FP, Cammisa FP Jr. Evaluation of the elderly patient with an abnormal gait. J Am Acad Orthop Surg. 2007;15(2):107-117.

Martin H, Lindblad B, Norman M. Endothelial function in newborn infants is related to folate levels and birth weight. Pediatrics. 2007;119(6):1152-1158.

Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G, Rosenberg IH. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev. 2007;16(7):1325-1329.

Nardin RA, Amick AN, Raynor EM. Vitamin B(12) and methylmalonic acid levels in patients presenting with polyneuropathy. Muscle Nerve. 2007;36(4):532-535.

Ochoa-Brust GJ, Fernández AR, Villanueva-Ruiz GJ, Velasco R, Trujillo-Hernández B, Vásquez. Daily intake of 100 mg ascorbic acid as urinary tract infection prophylactic agent during pregnancy. Acta Obstet Gynecol Scand. 2007;86(7):783-787.

Parekh N, Chappell RJ, Millen AE, Albert DM, Mares JA. Association between vitamin D and age-related macular degeneration in the Third National Health and Nutrition Examination Survey, 1988 through 1994. Arch Ophthalmol. 2007;125(5):661-669.

Pham DQ, Plakogiannis R. Vitamin E supplementation in Alzheimer’s disease, Parkinson’s disease, tardive dyskinsia, and cataract: Part 2. Ann Pharmacother. 2005;39(12): 2065-2072.

Riccioni G, Bucciarelli T, Mancini B, Di Ilio C, Della Vecchia R, D'Orazio N. Plasma lycopene and antioxidant vitamins in asthma: the PLAVA study. J Asthma. 2007;44(6):429-432.

Ronnenberg AG, Venners SA, Xu X, Chen C, Wang L, Guang W, Huang A, Wang X. Preconception B-vitamin and homocysteine status, conception, and early pregnancy loss. Am J Epidemiol. 2007;166(3):304-12. Epub 2007 May 2.

Sahin M, Tutuncu NB, Ertugrul D, Tanaci N, Guvener ND. Effects of metformin or rosiglitazone on serum concentrations of homocysteine, folate, and vitamin B12 in patients with type 2 diabetes mellitus. J Diabetes Complications. 2007;21(2):118-123.

Tamori A, Habu D, Shiomi S, Kubo S, Nishiguchi S. Potential role of vitamin K(2) as a chemopreventive agent against hepatocellular carcinoma. Hepatol Res. 2007;37 Suppl 2:S303-307.

Tecklenburg SL, Mickleborough TD, Fly AD, Bai Y, Stager JMAscorbic acid supplementation attenuates exercise-induced bronchoconstriction in patients with asthma. Respir Med. 2007;101(:1770-1778.

Triantafyllou NI, Kararizou E, Angelopoulos E, Tsounis S, Boufidou F, Evangelopoulos ME, Nikolaou C, Vassilopoulos D. The influence of levodopa and the COMT inhibitor on serum vitamin B12 and folate levels in Parkinson's disease patients. Eur Neurol. 2007;58(2):96-99.

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Review Date:
10/29/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

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Anemia

FitSugar — Wed, 08 Oct 2008 17:34:54 -0700

Overview

Signs and Symptoms
What Causes It?
What to Expect at Your Provider's Office
Treatment Options
Following Up
Special Considerations
Supporting Research

HEALTH GUIDE REFERENCE FROM A.D.A.M

Anemia is when a person does have enough red blood cells or the proper concentration of hemoglobin (iron-containing portions of red blood cells). These deficiencies occur when the body either does not make enough red blood cells or destroys too many red blood cells. One of the major functions of red blood cells is to carry oxygen throughout the body,. A decrease in red blood cells means the body's tissues don't get enough oxygen, causing the symptoms of anemia. There are several different types of anemia. The most common are iron deficiency anemia, megaloblastic anemia (caused by lack of some B vitamins), and anemia of chronic disease.

Signs and Symptoms

Symptoms of anemia can be mild, at first, and can be mistaken for other symptoms of other conditions.

Tiredness
Weakness
Shortness of breath
Pale skin
Lightheadedness
Headache
Feeling cold
Rapid heartbeat and chest pain

What Causes It?

Anemia may have the following causes.

Blood loss, including gastrointestinal blood loss (caused by ulcers, cancer, parasites), genitourinary blood loss (such as from heavy menstruation), or blood loss after surgery or regular blood donations
Diseases and conditions, such as congenital diseases (for example, sickle-cell anemia), malabsorption syndromes (for example, celiac disease), and other chronic conditions
Side effect of medication
Malnutrition
Iron, folic acid, vitamin B12, or other vitamin deficiencies
Pregnancy and breast-feeding
Excessive alcohol or drug use

What to Expect at Your Provider's Office

Anemia is often the result of an underlying disease. Your health care provider will have you blood examined in laboratory tests. If you are anemic, your health care provider will try to determine the cause to begin treatment.

Treatment Options

Treatment depends on the cause and severity of the anemia. Your health care provider may recommend changes in your diet to make sure you receive all of the nutrients you need for healthy blood formation, such as vitamin B12, iron, and folic acid. Your health care provider may also suggest nutritional supplements or medication. If your anemia is the result of an underlying disease, that disease must first be successfully treated.

Drug Therapies

Erythropoietin plus iron -- for anemia caused by chronic kidney failure
Corticosteroid medications (such as prednisone)
Immunosuppressant medications (such as azathioprine) -- for aplastic anemia

Surgical and Other Procedures

Removal of the spleen (splenectomy) -- may be necessary in cases of hereditary spherocytosis
Transfusions -- may help treat certain types of anemia, including anemia of chronic disease

Complementary and Alternative Therapies

Most cases of anemia will respond well to nutritional therapy. You should, however, already have the underlying cause of anemia diagnosed so you can begin the right treatment. For example, excess iron is toxic, and you should not take supplements unless you have iron deficiency anemia and your health care provider recommends them. Herbal and nutritional treatments may be helpful when used along with medical treatment.

Nutrition and Supplements

Ferrous fumerate, glycerate, or sulfate (50 mg three times per day for 3 - 6 months, or as prescribed) are the most absorbable forms of iron. All iron supplements can cause nausea, constipation, and heartburn. Taking a smaller dose three times a day may reduce side effects, as can taking iron with meals. If you miss a dose, don't take an extra dose the next time. Never take a double dose of iron. Keep iron supplements away from children. Even a little excess iron can be fatal.
Dietary sources of iron include red meat (especially calf liver), beans, beet greens, blackstrap molasses, almonds, and brewer's yeast. Green leafy vegetables contain both iron and folic acid (see below).
Vitamin C -- 250 - 500 mg twice a day to aid in absorption of iron. Dietary sources include citrus fruits and juices, tomatoes, broccoli, and cauliflower.
Vitamin B12 -- cyanocobalamine, 1,000 mcg via injection once a day for 1 - 2 weeks, then every 1 - 3 months; or orally, 1,000 - 2,000 mcg per day. Dietary sources include liver, meats, eggs, tuna, and cheese.
Folic acid (400 mcg - 1,000 mcg per day) -- for folic acid deficiency, which can cause anemia. Good food sources include green leafy vegetables, orange juice, and grains. Folic acid supplementation can mask vitamin B12 deficiency, so always take vitamin B12 when taking folic acid.

Herbs

Herbs can strengthen and tone the body's systems. As with any therapy, you should work with your provider to get your problem diagnosed before starting any treatment. You may use herbs as dried extracts (capsules, powders, teas), glycerites (glycerine extracts), or tinctures (alcohol extracts). People with a history of alcoholism should avoid using tinctures. Unless otherwise indicated, you should make teas with 1 tsp. herb per cup of hot water. Steep covered 5 - 10 minutes for leaf or flowers, and 10 - 20 minutes for roots. Drink 2 - 4 cups per day. You may use tinctures singly or in combination as noted.

You may be treated with the following herbal therapies for 1 -3 months and then reassessed.

Blackstrap molasses, also known as pregnancy tea (1 tbs. per day in a cup of hot water), is a good source of iron, B vitamins, and minerals. Blackstrap molasses is also a very gentle laxative.
Spirulina, or blue-green algae, may treat both microcytic and macrocytic anemias. Dose is 1 heaping tsp. per day.
Alfalfa (Medicago sativa), dandelion (Taraxacum officinale) root or leaf, burdock (Arctium lappa), and yellowdock (Rumex crispus) have long been used to fortify and cleanse the blood. For mild cases of anemia, they may help bring levels of hemoglobin into normal range. Dosage is 1 tbs. per cup of water. Simmer roots for 20 minutes and leaves for 5 minutes. You may use a single herb, or a combination of these four herbs.
Gentian (Gentiana lutea) is often used in Europe to treat anemia by stimulating the digestive system to more easily absorb iron and other nutrients. Add 1 tsp. powdered dried rhizome to 3 cups of water. Take 1 tbs. about a half hour before eating.

Homeopathy

Although few studies have examined the effectiveness of specific homeopathic therapies, professional homeopaths may consider the following remedies for the treatment of anemia based on their knowledge and experience. Before prescribing a remedy, homeopaths take into account a person's constitutional type -- a person's physical, emotional, and psychological makeup. An experienced homeopath assesses all of these factors when determining the most appropriate treatment for each individual.

A homeopath will usually consider anemia as symptomatic of an underlying condition, and treat that condition.

Ferrum phosphoricum -- for iron deficiency
Calcarea phosphorica -- particularly for children with nighttime bone aches, cool hands and feet, lack of energy, or poor digestion

Following Up

Maintaining a normal balanced diet is very important if a nutrition problem is causing your anemia. In addition, you should avoid both drugs that can cause stomach problems and too much alcohol if they are causing your anemia.

Special Considerations

Complications from anemia can range from loss of productivity due to weakness and fatigue to coma and death. Some neurologic changes caused by anemia are irreversible. Pregnant women need three or four times as much iron as normal. A folic acid deficiency during pregnancy can result in infants being born with neural-tube defects, such as spina bifida.

Supporting Research

Branch WT Jr. Office Practice of Medicine. Philadelphia, Pa: WB Saunders Company; 1994.

Carr AC, Frei B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr. 1999;69(6):1086-1107.

CDC Recommendations to prevent and control iron deficiency in the United States. Centers for Disease Control and Prevention. MMWR Recomm Rep 1998;47:1-29.

Elia M. Oral or parenteral therapy for B12 deficiency. Lancet. 1998;352:1721-22.

Fauci AS, Braunwald E, Isselbacher KJ, et al., eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill; 1998.

JAMA Patient Page. How much vitamin C do you need? JAMA. 1999;281(15):1460.

Johnston CS. Recommendations for vitamin C intake. JAMA. 1999;282(22):2118-2119.

Kelley WN, ed. Textbook of Internal Medicine. 3rd ed. Philadelphia, Pa: Lippincott-Raven; 1997.

Levine M, Rumsey SC, Daruwala R, Park JB, Wang Y. Criteria and recommendations for vitamin C intake. JAMA. 1999;281(15):1415-1453.

Tyler VE. The Honest Herbal: A Sensible Guide to the Use of Herbs and Related Remedies. 3rd ed. Binghamton, NY: Pharmaceutical Products Press; 1993.

Ullman D. The Consumer's Guide to Homeopathy. New York, NY: Penguin Putnam; 1995:181.

Review Date:
6/15/2006
Reviewed By:
Steven D. Ehrlich, N.M.D., private practice specializing in complementary and alternative medicine, Phoenix, AZ. Review provided by VeriMed Healthcare Network.

A.D.A.M. Copyright

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