Iron deficiency anemia
Don't be fooled by high ferritin
by Menaka Pai, MD and Armand Keating, MD
Vol.15, No.04, April 2007

How common is iron deficiency?
Iron deficiency is the most common nutritional deficiency and cause of anemia worldwide. In North America, it occurs in up to 11% of women and 4% of men. Certain groups are more prone to the condition, including toddlers, women of reproductive age, pregnant women, vegetarians and individuals from aboriginal communities.

How is iron stored in the body?
We like to think of iron storage the same way we do of our money. The body deposits this element into the liver, spleen and bone marrow. This pool of iron can be thought of as a mutual fund. It provides a stable backup supply from which the body can withdraw when there's increased demand. Iron is also found in circulating red blood cells. This functional pool is like the money in our wallets. We use it on a daily basis. Finally, iron is found in a transport pool, where it's linked to the molecule transferrin. The transport pool is like our chequing account -- transferrin transports iron between the storage ("mutual fund") and functional pool (the "wallet").

The average Canadian consumes 10 mg of iron daily. Of this, 1 mg is absorbed through the gut. Through the same route, 1 mg is lost each day. So under ideal circumstances, the body maintains a perfect iron balance -- far more perfect than our bank balance!

What are the causes of iron deficiency in adults?
This deficiency occurs when the body's demand outstrips its supply, and the perfect balance goes haywire. The most common cause of increased iron demand is iron loss. Women of reproductive age are at a high risk for iron deficiency because they experience iron loss in several physiologic ways. Every month, a woman loses approximately 15 mg of iron through menstruation. Lactation results in a loss of 0.5-1.0 mg every day, and a full-term pregnancy causes a loss of > 500 mg of iron. In men and nonmenstruating women, iron deficiency is never physiologic and should raise red flags. The most common cause for the condition in this age group is gastrointestinal (GI) loss from either occult malignancy or ulceration. This type of blood loss is often asymptomatic.

Inadequate iron supply can also contribute to iron deficiency, but it's rarely the sole cause. That's because the average Canadian diet is rich in bioavailable iron and iron-fortified foods. Iron malabsorption can occur, however, in patients with gastric surgery, atrophic gastritis or celiac disease.

When should we suspect iron deficiency?
Iron deficiency is an insidious process. It starts with iron depletion, where the body's storage pool is reduced, but the transport and functional pools are normal -- at this stage, patients are often asymptomatic. Eventually, the depletion progresses to iron deficiency anemia, in which all three iron pools dry up. The result is a microcytic, hypochromic anemia (see Figure 1). Only at this stage can overt symptoms develop.

Taking a history can provide some clues to iron deficiency anemia. Patients may complain of pallor, weakness, headache, palpitations, dizziness and irritability. If anemia develops rapidly, they may experience cardiac or cerebrovascular insufficiency. Iron deficiency usually develops slowly, however, so the hemoglobin can drop very low before severe symptoms appear.

The physical exam may unearth some unique clinical findings that differentiate iron deficiency from other anemias. Since iron compounds are responsible for the growth of epithelial tissues, some patients develop glossitis, angular stomatitis, gastric atrophy or "spooned" fingernails. These physical findings only appear in very advanced stages, and they're not sensitive. So if you don't find them, you can't rule out iron deficiency. One odd finding that's specific for iron deficiency is pagophagia -- an obsessive appetite for ice. This condition may be present in up to 50% of iron-deficient patients.

What investigations can help confirm the diagnosis?
The first test you should order is a complete blood count (CBC) and a blood film. The classic finding of iron deficiency anemia is microcytic, hypochromic anemia. Keep in mind, though, that anemia is the final stage in the iron deficiency spectrum. To diagnose the condition early, we need to detect low body iron stores before the patient develops florid anemia.

The serum ferritin is the single most useful blood test for assessing iron stores. A serum ferritin < 15 mg/L is virtually diagnostic of a depleted iron storage pool. Unfortunately, the serum ferritin isn't very useful if it's normal or high -- that's because ferritin is an acute-phase reactant. If the patient has a coexisting inflammatory condition, infection, liver disease or cancer, the ferritin will go up. This effect can mask iron deficiency.

Physicians commonly order the serum iron and the transferrin saturation to sort this situation out, but these tests are acute-phase reactants as well. They also vary with circadian rhythms and food intake, and can fluctuate by > 30% over the course of the day. This makes them even less useful than the ferritin. Recently, the serum transferrin receptor (sTfR) to ferritin ratio has been used to diagnose iron deficiency anemia in the setting of a high or normal ferritin, but the sTfR isn't widely available.

The most definitive test of iron deficiency is a bone marrow biopsy. The bone marrow is part of the iron storage pool, and if a patient is truly iron-deficient, it will contain no stainable iron. If your patient can't or won't have a bone marrow biopsy, a careful therapeutic trial of iron can help clinch the diagnosis.

What other diseases mimic iron deficiency?
Microcytic, hypochromic anemia with low serum ferritin is the classical presentation of iron deficiency. By evaluating the patient and the lab tests, you can differentiate it from other causes of anemia.

First, check the mean cell volume. If it's high or normal, iron deficiency anemia is less likely. Macrocytic and normocytic anemias have a diagnostic workup of their own. Once the anemia has been established as microcytic, measure iron stores with a serum ferritin level. In an otherwise healthy patient, a low ferritin indicates deficiency, and a high ferritin rules it out.

If the serum ferritin is normal or high but you still suspect iron deficiency, you should consider the person's general health. Are there other conditions that may be driving up the ferritin? If you believe the clinical picture reflects iron deficiency anemia, go ahead with a bone marrow biopsy or a therapeutic trial of iron.

If you're unsure whether or not you're dealing with iron deficiency anemia, consider other causes of microcytic, hypochromic anemia. These include rare conditions like thalassemia and sideroblastic anemia, which should be investigated by a hematologist. Anemia of chronic disease (ACD), a microcytic, hypochromic anemia caused by abnormal iron metabolism, is frequently encountered in primary care. The inflammation that drives ACD also drives the ferritin up. ACD should be suspected when you find a mild anemia and a normal or high ferritin in a patient with chronic infection, inflammation or malignancy. It can be very difficult to distinguish ACD from iron deficiency anemia, and sometimes the two conditions coexist. The best course of action is to reassess your patient, then do a bone marrow biopsy or proceed with a therapeutic trial of iron.

How do you confirm the cause of iron deficiency?
The investigation of iron deficiency is an excellent example of teamwork between primary care physicians, hematologists, gastroenterologists and gynecologists. Your diagnostic workup and decisions about specialist referral should be guided by a thorough history and physical.

During your clinical assessment, remember the balance between iron supply and demand. You can assess supply by taking a good dietary history. Meat, poultry and fish are excellent sources of bioavailable iron. Patients who only eat plant-based and iron-fortified foods are at a higher risk of iron deficiency. A history of gastrectomy, atrophic gastritis or gluten intolerance may point to problems with iron absorption. Increased iron demand should also be evaluated. You must search for blood loss -- a common cause of iron deficiency that can be quite subtle. Patients should have a rectal exam and be asked about bloody stool, abdominal pain, change in bowel habit and constitutional symptoms. These can all be clues to underlying hemorrhagic lesions or malignancies. In women, take a thorough menstrual and pregnancy history as well. The medication history should focus on drugs associated with blood loss, such as salicylates, steroids and non-steroidal anti-inflammatory drugs. Alcohol is another factor that can induce blood loss by causing gastritis. The family history should focus on bleeding disorders and malignancy.

Most iron-deficient women of reproductive age lose blood through heavy menses. If you suspect menorrhagia, prompt referral to a gynecologist is essential. Mild bleeding disorders (such as von Willebrand's disease and platelet dysfunction) can aggravate heavy menstrual periods. These problems can be worked up by a hematologist.

Men and postmenopausal women with iron deficiency are at high risk of being diagnosed with GI cancer in the subsequent two years. It's vital to rule this out. Screening for occult GI bleeding with a fecal occult blood test is insensitive, so refer your patient to a gastroenterologist instead. He or she can do a colonoscopy and upper GI endoscopy to look for ulcers and gastritis. The gastroenterologist may also elect to do a small bowel follow-through if these tests are negative.

Celiac disease is present in approximately 3% of iron-deficient patients, and is most common in white people. As it can present with very minimal symptoms, we draw immunoglobulin A (IgA) endomysial antibodies and IgA anti-tissue transglutaminase antibodies on patients with otherwise unexplained iron deficiency. We also ask the gastroenterologist to consider a small bowel biopsy to confirm the diagnosis.

What's the best way to treat iron deficiency?
You must replenish the patient's iron stores and simultaneously search for the underlying cause of the iron deficiency. The best way to replenish iron stores is with oral agents -- they're safe, effective and affordable. Iron-deficient patients need a daily supplement of 150-200 mg of elemental iron. It's important to know that different preparations contain different amounts of the metal. Ferrous gluconate has approximately 30 mg of elemental iron per tablet, ferrous sulfate around 60 mg and ferrous fumarate about 90 mg. No one preparation is better than any other; the higher content just minimizes the number of pills a patient has to take per day. We don't use the pricier enteric-coated or slow-release forms -- iron is best absorbed in the duodenum and proximal jejunum, and these preparations release it further down the GI tract. In terms of side effects, we're not aware of any differences between the preparations.

Most patients tolerate oral iron well. Approximately 10% experience GI symptoms such as diarrhea, constipation, nausea and epigastric discomfort. Lower GI complaints are usually mild, and we manage them symptomatically. We deal with upper GI symptoms by decreasing the daily dose or administering the supplement with meals. These strategies do make iron supplementation less effective though, so the treatment period may be prolonged.

We rarely use intravenous (IV) iron or blood transfusions to treat iron deficiency. The condition usually develops slowly, so there are few reasons to treat it quickly. Transfusions can be considered in the patient experiencing ischemic symptoms from anemia. IV iron is associated with anaphylaxis and serum sickness. It should only be considered in the patient with chronic uncontrollable blood loss, confirmed iron malabsorption or severe intolerance of oral iron. Intramuscular iron is not a preferred option as its mobilization is slow and incomplete, and the injection is quite painful.

How quickly does treatment work?
It's important to know the normal response to supplementation in an iron-deficient patient. This will help you in monitoring compliance and the ongoing iron balance. If you're using a therapeutic trial of iron, it will also tell you if you have the right diagnosis!

The first change seen with supplementation is an increase in reticulocytes. These young red cells in the patient's peripheral blood rise 3-5 days after therapy is started, peak after 8-10 days, and then decline. This is a sign that the functional pool of iron is being restored. Hemoglobin starts to rise within a week of starting therapy, and normalizes within 6 weeks. We usually continue iron supplementation for 4-6 months after the hemoglobin normalizes. This ensures that the storage pool has been adequately filled. Patients usually feel more energetic within days of starting therapy.

If a complete response to therapy doesn't occur in 6 weeks, consider noncompliance, ongoing blood loss, ongoing malabsorption or an alternate cause of anemia. Even if a response does occur within 6 weeks, remember that iron deficiency isn't a "final diagnosis." You must continue to search for, and attempt to treat, the underlying cause.

What should we tell our patients?
Patient education should focus on compliance and strategies to maximize iron absorption. We know that acids and vitamin C increase iron absorption, so we tell our patients to take their iron supplements with a glass of orange juice. Bases, tannins and non-absorbable chelators decrease absorption; we therefore discourage our patients from taking their iron supplements with antacids, food, tea, dairy products or calcium.

Can we prevent iron deficiency?
In 1998, the U.S. Centers for Disease Control and Prevention (CDC) released guidelines to address the screening and prevention of iron deficiency. Pregnancy is a huge drain on iron stores. Iron deficiency anemia is associated with adverse outcomes for mother and child, and iron supplementation is known to be safe. For these reasons, the CDC recommends that doctors screen for iron deficiency at the first prenatal appointment. Anemic women should be treated with full-dose oral iron, while non-anemic women should receive low-dose oral iron, i.e. 30 mg/day, as primary prevention. For women of reproductive age who aren't pregnant, the CDC recommends doing a CBC to screen for anemia every 5-10 years, and annually for women with risk factors for iron deficiency, such as multiple pregnancies or low-iron diets. Women of reproductive age should always be encouraged to eat iron-rich foods; a registered dietitian can be a good resource to help with the education. Men and postmenopausal women don't need screening for iron deficiency beyond the routine medical examination.

Menaka Pai, MD, received her medical degree from McMaster University in Hamilton, Ontario, where she went on to train in internal medicine. She is currently a Hematology Fellow at the University of Toronto.

Armand Keating, MD, FRCPC received his medical degree from the University of Ottawa and currently is Professor of Medicine, Epstein Chair in Cell Therapy and Transplantation and Director, Division of Hematology, University of Toronto.

feature image

Figure 1. Peripheral blood film depicting microcytic, hypochromic anemia due to iron deficiency.

CAUSES OF IRON DEFICIENCY

ELEMENTAL IRON IN DIFFERENT PREPARATIONS

click here to view the pdf of the above figure and tables

References:

Guyatt GH et al. Laboratory diagnosis of iron-deficiency anemia: an overview. J Gen Intern Med 1992;7:145-53.

Ioannou G et al. Iron deficiency and gastrointestinal malignancy: a population-based cohort study. Am J Med 2002;113:276-80.

Rockey DC. Occult gastrointestinal bleeding. Gastroenterol Clin North Am 2005;34(4):699-718.

National Institutes of Health Consensus Development Conference Statement 2004: Celiac Disease. Available at http://consensus.nih.gov.

Goddard AF et al. Guidelines for the management of iron deficiency anaemia. British Society of Gastroenterology. Gut 2000;46(Suppl4):iv1-iv5.

Centers for Disease Control and Prevention: Iron deficiency -- United States, 1999-2000. Morb Mortal Wkly Rep 2002;51:897-9.

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

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