CASE ONE

Betty is a 29 year old housewife with two children. She saw her gynecologist for a routine checkup and mentioned that her monthly menstrual periods were getting longer and heavier over the past year. She was also having unexpected extra periods during some months. Because of the extra blood loss, blood tests were done. Her doctor told her that her hemoglobin was 9.8 which is a sign of anemia. (Normal for women is over 12.) Further blood tests showed that she had a low iron level. She was placed on iron pills twice a day and a hormone to regulate her periods. Within two months she was back to normal and her anemia was corrected.

CASE TWO

Bill, a 54 year old carpenter was referred for evaluation of anemia. He was surprised to find that he was anemic when he failed blood work done as part of an insurance physical. He was referred to his family doctor who confirmed the abnormality and referred him to our gastroenterology practice. Bill had no real symptoms except he often was more tired in the evenings and fell asleep earlier than usual. His physical exam was normal except he was a little pale, but he normally had a pale complexion and thought this was normal. A repeat blood test showed that his Hemoglobin was 10.5 grams. (Normal is over 14.) This signifies that he had lost about a fourth of his blood. Blood tests for vitamin B12 and folic acid were normal, but a ferritin (iron) level was only 8. (Normal is over 30.) Suspecting, the loss of blood from his digestive tract, a colonoscopy examination was performed. A tumor was found in his right colon. Biopsies at the time of colonoscopy showed cancer cells and Bill underwent surgery to remove his right colon and the tumor. It had not yet spread outside the colon and with additional chemotherapy his long term prognosis is optimistic. He was given several months of therapy with iron supplements to correct his anemia.

These two cases are examples of iron deficiency anemia. This article was written to better explain more about this problem and its significance.

Oxygen Delivery Boys

First some background information. The human body is made up of billions of small cells which are grouped together in the various specialized organs such as the lungs, heart, liver, etc. These cells work behind the scenes 24/7 to keep you healthy and active. Day and night, they quietly perform many functions such as growth and repair of tissues, production of heat, motion, circulation, digestion, and so forth. Individually, each small cell is much like a tiny machine which requires many things to do its job - including fuel - and oxygen to burn that fuel. The fuel comes from the food that you eat in the form of fats, carbohydrates, and protein. The oxygen comes from the air that you breathe. The problem is: How do you deliver fuel and oxygen down to each and every cell?

The answer lies in your circulatory system, or bloodstream. Powered by your heart, this extensive series of arteries and veins carries blood to every cell of your body. With each heartbeat, your bloodstream gathers fuel from your digestive system and oxygen from your lungs and carries them both deep within your body - eventually down to each small cell. To maximize the delivery of oxygen, your blood contains specialized cells, called red blood cells. They are produced in the bone marrow and make up the majority of the cells in your blood. [The other two cell types are white blood cells that fight infection and platelets that help clot the blood.] As your blood constantly circulates, these red blood cells act like "oxygen delivery boys" picking up a load of oxygen as they travel through your lungs and dropping off the oxygen when they travel past the cells. They repeat the journey over and over again with each beat of your heart, thousands of times each day.

Red blood cells excel at oxygen delivery because they are made of a special pigment called hemoglobin which selectively binds oxygen molecules. Hemoglobin is mostly made of iron, a natural mineral. Just like a factory needs steel to make cars, your bone marrow needs iron to create hemoglobin and new red blood cells. But you need just the right amount. Too much iron is toxic to the body and can lead to organ damage. However, if iron levels are too low, hemoglobin production drops and fewer red blood cells are created.

When the number of red blood cells falls below normal, this is called anemia. There are many types of anemia, but that due to insufficient iron is, of course, called iron deficiency anemia. It has nothing to do with leukemia or cancer of the bone marrow. Iron deficiency anemia is universally the most common form of anemia affecting about 5% of American women and 2% of men. It is nothing new for its manifestations have been found described in manuscripts that are more than 3,000 years old.

What are the symptoms of iron deficiency anemia?

One problem is that iron deficiency anemia is very sneaky. It usually develops very slowly over a period of many months or even years. There are no symptoms in the early stages. By the time you do have symptoms, the anemia may be severe. When present, symptoms of iron deficiency include fatigue, muscle weakness, rapid heartbeat, and shortness of breath. It can cause chest pain, as the heart is forced to work harder and faster to compensate. Other signs of iron deficiency anemia are a pale complexion and hair loss. Some patients report a sore red tongue and brittle fingernails.

There is one symptom of iron deficiency anemia that is quite unusual. When specifically questioned, some patients report odd food cravings, a condition called pica. These individuals may find themselves uncontrollably eating large amounts of ice, starch, and even dirt and clay. When the anemia is treated, these odd cravings disappear. The cause is not known.

What causes iron deficiency?

It's all based on a delicate balance between how much iron enters your body and how much you lose daily. Iron is normally obtained through the food in your diet and by the recycling of iron from old red blood cells. Each day, you absorb about 1 mg of iron from your diet and lose about an equal amount in the stool and sweat. If you don't absorb enough iron from your diet, the iron level will slowly drop and you will eventually become anemic. On the other hand, if you lose more iron than you absorb, the iron level will also drop causing anemia. Thus, there are the two major ways that someone becomes iron deficient.

1. Not absorbing enough iron from the diet The absorption of iron from the diet can be limited by what you eat or by how well your intestines absorb iron that is in your food. Iron deficiency can occur in strict vegetarians who eat no red meat or eggs, but this in an uncommon cause of iron deficiency anemia since dark green leafy vegetables do contain iron. Another group of individuals at risk for iron deficiency anemia are those who have had surgery on their stomach or small intestine and those with certain digestive ailments such as Celiac sprue and Crohn's disease. All of these conditions can impair iron absorption. In underdeveloped countries, iron deficiency is most commonly caused by malnutrition.

2. Losing iron faster than you are absorbing it The most common cause for iron deficiency anemia, however, is chronic blood loss. When you lose blood, you are doubly damaged. Not only do you lose actual red blood cells, but, since blood contains iron, you also lose the iron that your bone marrow needs to make new ones. The best example of this is menstruation. During their childbearing years, women have chronic blood loss through their monthly menstrual period, placing them at higher risk for iron deficiency anemia than men. In fact, menorrhagia (heavy monthly periods) is the most common cause of iron deficiency anemia in pre-menopausal women. Multiple pregnancies and breast-feeding can compound iron deficiency. That is why iron supplements are important for women, especially during pregnancy.

So menstruating women are often a little anemic. However, all men and post-menopausal women have no reason to develop iron deficiency anemia since they do not have monthly blood loss. Iron deficiency anemia in a man or post-menopausal woman suggests that they are losing blood from somewhere else - most often from the digestive system. In fact, it is quite common to acquire significant iron deficiency anemia due to slow chronic loss of blood from the digestive tract. It only takes about 1 to 2 teaspoons of blood loss daily to exceed iron absorption. If the amount of blood lost each month is this small, the blood is digested with the food, mixed with the stool, and not readily visible. So you can be losing small amounts of blood each day and have bowel movements that look entirely normal.

This slow invisible loss of blood is called occult bleeding. Possible causes of occult blood loss from the digestive system include a large hiatal hernia, acid reflux, peptic ulcers, gastritis, stomach and colon polyps, stomach and colon cancer, colitis, hemorrhoids and others. The point is that if you are non-menstruating woman or a man and you have iron deficiency anemia, you need to see your doctor. He will often refer you to a digestive disease specialist, or gastroenterologist, for further evaluation.

1. Are you really anemic?

2. If so, is the anemia due to iron deficiency, or something else?

3. If iron deficiency is present, is it due to low iron intake or chronic blood loss?

QUESTION #1 - ARE YOU ANEMIC?

1. Hematocrit measures what percent of your blood is made up of red blood cells and what percent is liquid, or plasma. When you are anemic, your blood has contains less red blood cells and more liquid, the Hematocrit reading would be lower than normal - a sign of anemia. For practical purposes, anemia in men is diagnosed when the Hematocrit is less than 40% and in women when it is less than 37%.

2. Hemoglobin measures how much Hemoglobin pigment is present in the blood - expressed in grams of hemoglobin per 100 cc of blood. A low Hemoglobin is another sign of anemia. Men with Hemoglobin measurements less than 14 and less than 12 for women are considered anemic. (Together the Hemoglobin and Hematocrit are often referred to as the "H & H.")

QUESTION #2 - COULD IT BE DUE TO IRON DEFICIENCY?

If the Hemoblogin and Hematocrit is low, anemia is indeed present. Now your doctor can use other elements of the CBC to further characterize the type of anemia. One is the Mean Corpuscular Volume, or MCV, which represents the average of the size of all of the red blood cells in the sample of blood. The normal MCV for an adult is 80 fl to 100 fl and is termed normocytic ("normal cells"). A low MCV (below 80) is termed microcytic ("small cells"), and a high MCV (over 100) is considered macrocytic ("large cells"). A low MCV is often seen in cases of iron deficiency anemia. So, if you are anemic and your MCV is low, iron deficiency is very possible. (Another cause of a low MCV is Thalassemia major, an inherited anemia. See sidebar)

Often the doctor orders a blood smear test. A drop of blood is thinly smeared on a glass microscope slide and stained with special chemicals. This allows the lab technician to view the red blood cells directly using a powerful microscope. In the case of iron deficiency anemia, the red blood cells are often pale due to the lack of hemoglobin. This condition is called hypochromia. Pale red blood cells on a blood smear suggests iron deficiency anemia. Note the difference between the normal blood smear below and that from a case of iron deficiecny anemia:

The CBC also includes a measurement of the other cells in the blood. In iron deficiency anemia the white blood cells are usually unaffected and the platelet count tends to rise somewhat. A low platelet count or abnormal WBC count would suggest an alternative cause for anemia than iron deficiency.

If a CBC shows that you have an anemia (low H&H) and the red blood cells are shrunken (low MCV, microcytic) and pale on smear (hypochromic), what you have is called a "hypochromic microcytic anemia," the hallmark of iron deficiency. To confirm this, your doctor can order further blood tests which directly measure the amount of iron in your body.

A direct measurement of iron in the blood is often performed, but is not reliable for assessing iron deficiency since it can fluctuate for many reasons. It is possible to have low body iron stores, but a normal level in the blood. More reliable is the serum Ferritin level. This is a sensitive test for iron deficiency because it accurately reflects body stores and is usually the earliest laboratory measure to change in iron deficiency. It is not affected by day to day fluctuations in iron intake. Ferritin levels between 30 mcg/L and 300 mcg/L are considered normal. A serum ferritin below 15 mcg/L is proof that the patient is iron deficient.

QUESTION #3 - IF IRON LEVEL IS LOW, WHAT IS THE CAUSE?

Now the question comes up --- If you are iron deficient, what is the cause of the iron deficiency? Where did the iron go? Is the cause a poor intake/absorption of iron? Or is the cause a slow leak - and loss of iron/blood from the body? These are important questions.

Looking for the "leak"

If blood tests show that an individual has an anemia which is due to iron deficiency and if there is no obvious source of blood loss (such as monthly menstrual periods) and no reason to suspect poor iron absorption, other possible sources must be considered. In this circumstance, the digestive tract often becomes the likely suspect. This is because it is possible to lose small amounts of blood daily in the stool, but not see it because the blood is digested with the food. In fact, you can be losing blood every day and not know it.

One simple test is a chemical test of a stool specimen for hidden, or occult, blood (Hemoccult, Seracult). If the stool test shows hidden blood, then it is important to evaluate the digestive tract. The problem lies in a normal stool test since bleeding from the digestive tract is usually intermittent. If the stool is tested on a "non-bleeding day," it will give a false good impression. This happens about 40% of the time, so a Hemoccult test only helps if it is abnormal. A normal can not be trusted.

What can cause blood loss from the digestive tract?

On average, the adult digestive tract is a thirty foot long hollow "pipe" that travels from mouth to anus. It has three major sections.

• The upper digestive system = the esophagus and stomach
  
• The small intestine which is where the food is digested
  
• The lower digestive system = the large intestine (colon)
  

In general, it is unusual to find a source of significant blood loss in the small intestine, so the investigation usually first focuses on the upper and lower digestive system.

The upper digestive system is best examined directly by performing a special "scope" test called a gastroscopy. With this test, the doctor can look for ulcers, hiatal hernia, stomach polyps, stomach cancer, and gastritis all of which could account for a slow "leak" of blood.

Similarly, the colon is best seen by performing a colonoscopy examination. During this test, the doctor is looking for possible colon polyps, colon cancer, colitis, and leaky blood vessels in the colon called angiodysplasia. Not to be pessimistic, but it is general rule in medical school that if a man or postmenopausal woman presents with iron deficiency anemia, a high priority is to rule out the possibility of colon cancer which often has no other symptoms.

If gastroscopy and colonoscopy do not determine the source of blood loss, a barium x-ray of the small intestine (small bowel series) is sometimes performed to look for problems there. Sometimes patients are referred to a large hospital center for a special test called small intestinal enteroscopy. This requires a special extra long gastroscope not usually available in a community hospital setting.

Treatment

After your doctor finds and treats the cause of your iron deficiency, he can prescribe appropriate therapy to get your iron levels back to normal and correct the anemia. Eating more iron-rich foods is often suggested. These include raisins, meats (liver is the highest source), fish, poultry, eggs (yolk), legumes (peas and beans), and whole grain bread. While increasing the iron content of your diet can be helpful, this is an inefficient way to boost your iron stores. In fact, it takes about 11 pounds of red meat to provide the same iron content as one high dose iron supplement. So, if you have iron deficiency anemia, your doctor will probably also suggest an iron supplement. These come in two basic forms.

Multivitamins with iron
The most common are multivitamin supplements that also contain a low dose of iron for daily maintenance. Many brands are available. These are best for women who are not anemic but have extra blood loss from monthly periods. Extra iron is also needed during pregnancy and lactation because normal dietary intake cannot supply the required amount. The usual dose of iron in these supplements is 10 - 20 mg of ferrous sulfate which delivers about 1 - 2 mg. of elemental iron to your system.

High dose iron supplements
When treating significant iron deficiency anemia, a higher dose supplement is required to maximize iron absorption. Many brands are available. Most are inexpensive, effective, and available without a prescription. Here are some examples:

Generic ferrous sulfate
The most common form and widely prescribed iron preparation is generic ferrous sulfate. The usual dose is 325 mg per capsule which delivers about 65 mg of elemental iron. This formulation is cheap and effective, but sometimes irritates the stomach.

Feosol

Another brand name that is "slow-release" and somewhat gentler on the stomach and often recommended is FeoSol. This is a non-prescription drug that comes in three forms:

FeoSol capsules
Each Feosol capsule contains 45 mg of pure elemental iron and is supplied in boxes of 30 or 60 capsules in a child-safely blister pack.

FeoSol tablets
Each Feosol tablet contains 65 mg. of elemental iron, the same as 325 mg. of ferrous sulfate. They are supplied in boxes of 100 tablets in a child-safety blister pack.

Feosol Elixir
FeoSol elixir, is an unusually palatable iron elixir, which provides 45 mg. of elemental iron in 1 teaspoon. It is supplied in 16 oz child-resistant bottles which contain 94 doses.

SlowFe
This preparation of ferrous sulfate is packaged in a wax matrix which slows the release of iron minimizing gastric side effects. Each tablet contains 160 mg of dried ferrous sulfate equivalent to 50 mg. of elemental iron. They are supplied in child-resistant blister packs of 30, 60, and 90 tablets.

How to take iron supplements
Usually your doctor will prescribe one to three tablets daily depending on the severity of the anemia and your tolerance to the drug. Ideally you should take iron supplements on an empty stomach since this increases iron absorption and effectiveness. This usually means 1 or 2 hours before a meal. However, most patients find they must take their iron pills with food to minimize side effects. Common side effects include upset stomach with diarrhea, constipation, nausea, or abdominal distress. The nausea and abdominal pain can be lessened by reducing the dose or taking the medication after meals. The iron will still be absorbed, but at a lower rate.

Milk and antacids may interfere with absorption of iron and should not be taken at the same time as iron supplements. Vitamin C helps your body absorb iron. Make sure to get your daily allowance. If you eat at least three servings of vegetables and two servings of fruit each day, especially citrus fruits, you're probably getting enough. You can also raise your vitamin C intake with a one-a-day multivitamin. Do not be alarmed if your bowel movements turn dark green or black when taking high dose iron supplements. This is normal and has no significance.

Drug Interactions
The effect of iron on the absorption of other drugs is also significant. Iron taken simultaneously with certain medications such as Levodopa (Atamet, Sinemet, Larodopa, Dopar), Tetracyline (Achromycin, Topicyline), and Norfloxacin (Noroxin, Chibroxin) can reduce their absorption by up to 90%. If you are on these drugs, take the iron supplement at least 2 hours apart from these medications.

Iron shots
If a patient can not tolerate oral iron supplements, INFeD iron shots are available. On average 5 - 10 shots are given over the course of several weeks. These shots are expensive, cause a permanent brown stain at the injection site, and there is a small, but real, risk of serious allergic reactions. Because of this, iron shots are seldom used and reserved for unusual cases.

Blood transfusions
Rarely, iron deficiency anemia may become so severe that it is life threatening. In these cases, you can't wait two months for the bone marrow to correct the anemia. The doctor must prescribe a series of blood transfusions to raise the blood count immediately. This is more likely to be necessary if the hemoglobin is less than 8 gm and the patient has a history of heart disease, trouble breathing, or at risk for a stroke. Patients and doctors are always concerned about the risk of transfusion related blood reactions and transmission of infections such as hepatitis or AIDS. Modern blood bank screening techniques minimize these risks, but they are still present to a small degree. Blood transfusions are only used when the anemia is felt to be potentially life threatening, in which case the benefit outweighs the risk.

How long to take iron
When an individual with iron deficiency anemia begins iron supplements, the bone marrow acts like a shut-down factory going back to work on overtime. The new iron is used to make more hemoglobin which allows red blood cell production to soar. Most patients will see their anemia improve within a few weeks with a gradual rise in the Hemoglobin and Hematocrit blood test. The MCV index should rise as shrunken iron deficient red blood cells are replaced with healthy full sized cells. Within 8 weeks the anemia is usually gone. However, treatment should continue daily until the body iron stores are fully replenished. This may take up to six months in severe cases. One way to see that this has been accomplished is the ferritin level. A ferritin level over 50 assures that the body iron stores have been replenished.

Prevention of iron deficiency
The daily dietary iron requirement for all men and women after menopause is about 1.0 mg per day. The average American diet is usually enough to meet these needs. Men do not need extra iron supplements. If they take a multivitamin-mineral supplement, it should not contain iron.

Menstruating and lactating women, however, need 2.0 mg of iron per day. During pregnancy, the requirement rises to about 3.0 mg. per day. Since the intestines absorb only 10% of the iron in the diet, an oral intake of 20 mg to 30 mg of iron is needed to meet these requirements. You should not take doses higher than this without talking with a doctor first. There is no normal mechanism for your body to excrete excess iron. Taking too much iron can actually be unhealthy and cause long-term negative effects.


Individual	Recommended iron daily	Supplement
All Men, Post-Menopausal Women	1 mg elemental iron daily	None
Menstruating Women	2 mg. elemental iron daily	Multivitamin with iron
Pregnant Women	3 mg. elemental iron daily	Multivitamin with iron
Iron Deficiency Anemia	45 - 195 mg. elemental iron daily	High dose iron supplement


Iron can be deadly
If you have iron-containing vitamins or higher dose iron supplements, be sure to keep them out of the reach of children. Iron is poison for small children. In fact, iron is the leading cause of poisoning deaths in children under six.

• Keep pills in their original childproof bottle and close it tightly right after use.

   

• Put the bottle in an out-of-reach place right after use.

   

• Keep the bottle out of sight of children at all times.

Summary
Iron deficiency anemia is the most common form of anemia and may occur due to poor iron intake or as a result of chronic blood loss. It has nothing to do with leukemia. It usually develops silently over a long period of time. It is expected in women of childbearing age due to iron losses from menstruation, pregnancy, and breast-feeding. However, iron deficiency anemia in a man or a post-menopausal woman is often a sign of chronic blood loss from the digestive tract. Even mild cases warrant careful investigation to rule out colon cancer, peptic ulcer disease, and other causes of occult bleeding. The underlying cause must be treated and iron stores replenished with iron supplements. Most patients respond well to oral iron supplements.