Iron Deficiency Anemia

Iron deficiency anemia is a condition where the body does not have sufficient iron to produce enough hemoglobin (Hb) for healthy red blood cells. It is characterized by the presence of microcytosis, or small red blood cells (RBCs), as a result of decreased Hb production. The Hb molecule is made with iron, and is a required component of RBCs; within the Hb molecule, it is the iron atoms that carry oxygen to the body’s tissues.^[1]

While a person can often have no symptoms of iron deficiency anemia, weakness, fatigue, pallor (looking pale), irritability, headache, and poor exercise tolerance can be present. Pica (craving and eating for non-nutritive substances) is sometimes present as well, particularly for ice, and even clay or soil.^[2][3]

Anemia is defined as a Hb less than 12 grams per deciliter of blood (g/dL) in non-pregnant women, less than 11 g/dL in pregnant women, or under 13 g/dL in men.^[4][1][2]

Iron deficiency is the most common cause of anemia. Serum ferritin testing is recommended in patients with anemia to diagnose iron deficiency, as it has good accuracy compared to the (invasive) gold standard for diagnosis of bone marrow biopsy. It is the best biochemical test to indicate iron stores, and a ferritin level below 30 micrograms per liter of blood (µg/L) can indicate iron deficiency in anemia.

Serum ferritin is also an acute phase reactant — in other words, a marker of inflammation — therefore, C-reactive protein should also be measured to rule out a false elevation of ferritin from an inflammatory condition or infection. Depending on the condition, a cutoff value of less than 100 µg/L may be used for ferritin.^[4][5][2]

Iron deficiency anemia may also show the following signs on bloodwork:

• Mean corpuscular volume (MCV), a measure of RBC size: less than 80 femtoliters (fL)
• Mean cell hemoglobin (MCH), a measure of RBC iron content: less than 25 g/dL
• Percentage transferrin saturation less than 16% (or <20% in the presence of inflammation)^[6][5][2]

In addition: serum transferrin may be high, serum iron may be low, and total iron-binding capacity may be high.^[7][8]

If iron deficiency anemia is diagnosed, and the clinician suspects it may have a gastrointestinal cause, then tests such as a urea breath test (for H. pylori infection), serologic testing for celiac disease (tissue transglutaminase IgA), fecal occult blood testing (i.e., stool sample), upper endoscopy (i.e., viewing the esophagus, stomach, and upper intestines), or colonoscopy may also be performed to investigate for causes of blood loss.^[4][7]

The first-line therapy for iron deficiency anemia is oral supplementation.^[9] This therapy can even be effective in the demographic with the highest daily iron requirement: pregnant women; oral iron, when taken during pregnancy, was found to reduce maternal iron deficiency anemia and low birthweight (a side effect of maternal iron deficiency anemia).^[10]

A common form and dose of oral iron is ferrous sulfate at 100–200 milligrams per day, though there’s no evidence to suggest any particular iron preparation is more effective than another. Lower doses of iron may be equally effective while reducing adverse effects.^[9][11][12]. Some studies suggest that alternate-day dosing may be superior to consecutive-day dosing for increasing iron absorption.^[9]

Common side effects of iron supplementation are constipation, abdominal discomfort, nausea, and vomiting. Other oral forms, such as ferrous fumarate, ferrous gluconate, or iron suspensions, may be tolerated better, though there is inconsistent evidence.^{[7][2][1][13]} Enteric-coated iron supplements may reduce gastrointestinal side effects, but have lower absorption.^[7]

Supplementation with algae such as spirulina and chlorella might improve iron deficiency, though most research is in rats.^[14][15][16] One human trial showed that spirulina-containing flour benefitted the iron status and survival rates of infants (aged 6-24 months) when compared to flours without iron. However, the study participants were malnourished infants in Kenya who were hospitalized, decreasing applicability of results to other populations.^[17]

Iron supplements will often include vitamin B12 and folate, since iron deficiency can mask symptoms of a deficiency of either of these vitamins. Vitamin B12 and/or folate deficiency can cause a dysfunction of RBCs known as macrocytic anemia (where RBCs are enlarged), but this can be masked by iron deficiency (which would typically make RBCs smaller).

It has been shown that individuals with iron deficiency anemia have higher levels of oxidative stress and lower levels of endogenous antioxidants. Therefore, supplementing with antioxidant vitamins (e.g., vitamin C, vitamin E, and beta-carotene) may be considered in iron deficiency anemia.^[18]

Dietary counseling to increase iron intake can be effective at prevention or treatment of anemia in pregnant women. Counseling was typically given over a period of several months, and was found to be effective whether focusing only on iron intake, or several nutrients in addition to iron (such as vitamin B12 and folate).^[19]

Supplementation with ascorbic acid (vitamin C) in a dose of 250–500 milligrams twice per day is often recommended to increase iron absorption due to its acidic nature, though it is uncertain whether this ultimately increases the effectiveness of treatment for iron deficiency anemia.^[2][7]

Supplementation with high amounts of calcium, zinc, or magnesium in iron deficiency is cautioned against, as these may reduce iron absorption.^[20]

In more serious cases of iron deficiency anemia, erythropoiesis-stimulating agents (ESAs) may be used. ESAs are medicines that help the bone marrow to produce red blood cells; they’re often used in conjunction with oral iron therapy for people who also have a condition such as chronic kidney disease that is causing their iron deficiency anemia. Blood transfusions may also be used; they rapidly elevate red blood cells and iron in the body, but this procedure is rare and only used for serious cases of iron deficiency anemia.^[21]

Maintenance of iron-related blood markers requires a positive iron balance — iron absorption through dietary sources needs to be greater than the amount of iron we lose. It is normal to lose a small amount of iron per day,^[4] though a daily blood loss greater than 5-10 milliliters per day exceeds the amount of iron that can be absorbed from the average diet.^[7] The following are potential causes of iron deficiency anemia, since they can affect either iron loss or iron absorption. These are listed in approximate order of decreasing prevalence:

• Menstruation, especially if heavy
• Frequent and long-term use of non-steroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen (Advil), since this often causes bleeding in the gastrointestinal tract
• Celiac disease^[2]
• Stomach ulcer from H. pylori infection
• Blood donation
• Gastric bypass surgery
• Inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease.^[2][7]

Certain medications may reduce iron absorption, such as antacids, H₂ blockers, and proton pump inhibitors, since these reduce acidity in the stomach.^[7]

The presence of iron deficiency anemia in people without a menstrual cycle, especially in those over 50 years old, can be concerning since there may be blood loss occurring from a serious issue like gastric or colorectal cancer.^[7][2]