Iron deficiency anemia overview

# Overview
Iron deficiency anemia occurs when body iron stores are inadequate to meet normal metabolic demands of the body. It is the most common cause of microcytic anemia.
Iron deficiency anemia occurs in the setting of blood loss, insufficient dietary intake or poor oral absorption of iron from food. Symptoms of iron deficiency anemia including fatigue, weakness, shortness of breath, lightheadedness, and pallor. Twenty percent of all women of childbearing age have iron deficiency anemia, compared with only 2% of adult men. The principal cause of iron deficiency anemia in premenopausal women is excessive blood loss during menses. In post menopausal women and men, the main cause of iron deficiency are digestive tract diseases.
Iron deficiency anemia is the final stage of iron deficiency. When the body has sufficient iron to meet its needs (functional iron), the remainder is stored for later use in the bone marrow, liver, and spleen. Iron deficiency ranges from iron depletion, which yields little physiological damage, to iron deficiency anemia, which can affect the function of numerous organ systems. Iron depletion causes the amount of stored iron to be reduced, but has no effect on the functional iron. However, a person with no stored iron has no reserves to use if the body requires more iron. In essence, the amount of iron absorbed by the body is not adequate for growth and development or to replace the amount lost.

# Historical Perspective
Iron deficiency anemia was discovered in 1852 by Karl Vierordt and his student H. Welcher.

# Classification
There is no established system for the classification of iron deficiency. However, based on the pathology, it can be divided into functional and absolute iron deficiency.

# Pathophysiology
Iron homeostasis is maintained by a balance of iron absorption and iron loss. Iron absorption is a more active process and is mainly responsible for regulation of iron balance. The absorption of iron is highly regulated by hepcidin, a protein secreted by hepatocytes.
Iron is absorbed in ferrous form (Fe2+) in the small intestine via divalent metal transporter (DMT1). After absorption, depending on iron levels in the body, iron can be sequestered in ferritin or bound to transferrin by ferroportin. Once bound to transferrin, iron is transported to cells that require iron. Iron enters cells when transferrin binds to transferrin receptor (TfR).
Iron deficiency occurs in three stages. In the prelatent stage, ferritin is low but serum iron levels are normal. In the latent stage, transferrin saturation and serum iron are also low in addition to low ferritin. In the last stage, hemoglobin level is below normal along with depletion of iron stores and drop in serum iron and transferrin saturation.

# Causes
In developed nations, the main cause of iron deficiency anemia is blood loss. Bleeding from any source can cause iron deficiency anemia. Obvious causes of blood loss like menorrhagia, hematemesis, melena, hematuria, multiple child births, frequent blood donations can be easily recognized with history alone. Occult blood loss from causes like GI bleeding, parasitic infestations etc may be overlooked.
Inadequate dietary iron is the most common cause of iron deficiency anemia in resource poor countries. It is also the most common cause of iron deficiency anemia in toddlers. In toddlers, poor nutritional practices like excessive cow milk intake or snacking contribute to iron deficiency.
Malabsorption due to celiac disease, atrophic gastritis, Helicobacter pylori infection, post-bariatric surgery can also cause iron deficiency.
Drugs which suppress gastric acid can also impair absorption of iron as iron requires an acidic medium for absorption. Certain antibiotics like quinolones, doxycyline, chrloramphenicol etc also diminish the absorption of iron.
Chronic conditions like chronic heart failure, CKD, inflammatory bowel disease, malignancy, rheumatoid arthritis are also associated with iron deficiency anemia.
Other less common cause of iron deficiency include urinary and pulmonary hemosiderosis and genetic conditions like IRIDA due to TMPRSS6 mutations.

# Differentiating Iron Deficiency Anemia from other Diseases
Iron deficiency anemia and Thalassemia Minor present with many of the same lab results.  It is very important not to treat a patient with Thalassemia with an iron supplement as this can lead to hemochromatosis (accumulation of iron in the liver)  A hemoglobin electrophoresis would provide useful evidence in distinguishing these two conditions, along with iron studies.

# Epidemiology and Demographics
According to WHOs Global Burden of Disease Project 2000 (GBD 2000), iron deficiency is responsible for 841,000 deaths worldwide with the major burden of mortality seen in Africa and parts of Asia.
In the US, iron deficiency is seen in 9% of toddlers between age 1 and 2 years. Compared to white toddlers, Hispanic toddlers are twice as likely to have iron deficiency.
The prevalence in adolescent girls and women in reproductive age group is between 9% to 11%. It is most commonly seen in multiparous women from low income minority populations. In males, it is seen in around 1% of population with slightly high prevalence of 2 - 4% in middle aged and older men.
There is a positive correlation between obesity and the risk of developing iron deficiency.

# Risk Factors
Risk of iron deficiency anemia is more in those individuals who consume less iron in diet and who are at increased risk of bleeding.

# Screening
Screening is recommended in women of reproductive age and toddlers.

# Natural History, Complications, and Prognosis
Untreated iron deficiency anemia is associated with significant cognitive impairment and decreased work capacity and quality of life.
During pregnancy, untreated iron deficiency can affect fetal brain maturation and predispose the newborn to iron deficiency and low birth weight. Maternal adverse outcomes include depression, increase risk of sepsis and maternal mortality.
In patients undergoing cardiac or abdominal surgery, pre operative iron deficiency is associated with poor outcomes. In patients with heart failure, untreated iron deficiency can cause an increase in mortality.
If treated with iron supplementation, the prognosis is excellent.

# Diagnosis

## Diagnostic criteria
Iron deficiency anemia is diagnosed on the basis of results of CBC, peripheral blood film and iron studies. A normal hemoglobin does not rule out iron deficiency. Iron deficiency is diagnosed when serum ferritin is < 30ng/mL.

## History and Symptoms
Majority of symptoms are non specific and include weakness, fatigue, dyspnea on exertion, irritability, poor concentration and decreased exercise capacity. These are attributable to low oxygen delivery to tissues and decreased activity of iron containing enzymes.
Pica occurs in approximately half of these patients and pagophagia (craving for ice) is quite specific for iron deficiency.
Patients may have a history of dry mouth, hair loss, dysphagia, brittle fingernails and restless leg syndrome
Beeturia is a finding which is not specific for iron deficiency but is increased in these individuals. It is the result of a change in GI function due to severe Iron deficiency. The urine turns red following ingestion of beets.
Physical examination can be normal or show dry skin, atrophic glossitis, cheilosis, pallor and koilonychia(spoon shaped nails). Cardiac auscultation may reveal systolic murmur.

## Physical Examination
Physical examination may reveal pallor, koilonychia (spoon shaped nails), cheilosis, atrophic glossitis, dry skin and systolic murmur on cardiac auscultation.

## Laboratory Findings
The first step in diagnosis is ordering a CBC, peripheral smear and serum ferritin. Low serum ferritin is only seen in iron deficiency anemia but high ferritin can be seen in many chronic disorders.  Absolute iron deficiency is diagnosed with a serum ferritin of < 30ng/mL. A normal hemoglobin does not exclude iron deficiency as hemoglobin does not become low till a significant percentage of body iron is depleted.
Uncomplicated iron deficiency can be diagnosed by assessing standard iron parameters, such as serum ferritin and transferrin saturation.
Serum iron varies during the day and is influenced by diet. A fasting sample should be obtained in the morning. Plasma iron is reduced as the iron in the body is exhausted. Total iron binding capacity (TIBC) is elevated in iron deficiency anemia.
Serum transferrin is raised in iron deficiency anemia. Transferrin saturation index (TSAT) is the ratio of serum iron to TIBC. It is one of the earliest biomarker of ID and is useful when serum ferritin is unequivocal. A decrease (< 20%) indicates ID, either absolute or functional.
Soluble transferrin receptor (sTfR) is a fragment of membrane receptor for transferrin. It is elevated in iron deficiency because of upregulation of transferrin receptors. It can help differentiate between absolute(increased sTfR) and functional ID( normal sTfR).
sTfRFerritin index is the ratio of sTfR to serum ferritin. It is also considered a good indicator for evaluation of iron deficiency.
Other tests available for evaluating iron status include Zinc protoporphyrin/heme ratio and reticulocyte hemoglobin content.

## Treatment

## Medical Therapy
Iron supplementation is available in oral and IV forms. Oral iron is readily available, inexpensive, effective, safe, and convenient. Some of the available formulations include ferrous sulfate, ferrous fumarate, and ferrous gluconate. GI side effects are seen in up to 70% of the patients taking oral iron, leading to noncompliance with treatment. GI symptoms can be minimized by the use of chelated forms of iron. Enteric-coated tablets lead to poor absorption and should not be used.
Intravenous iron is available in many forms, such as ferric carboxymaltose, ferric gluconate, ferric/iron sucrose, ferumoxytol, and low-molecular-weight iron dextran. Response to IV iron should be checked to establish the need for further supplementation six to eight weeks after initial iron replacement.
There is a very low risk of allergic reactions with all IV iron formulations. Premedication with antihistamines does not prevent infusion reactions and should not be given. Patients with a history of asthma or drug allergies should receive steroids prior to infusion.
In pregnancy, oral iron is given during the first trimester as the safety of IV iron in the first trimester has not been established.
Generally, oral iron is given to pregnant women if it can be tolerated. Exceptions include women with severe anemia, women with IBD, and those who have undergone bariatric surgery. In these patients, IV iron is preferred. All IV forms have equal efficacy and safety except for some formulations of ferric gluconate which contain benzyl alcohol as a preservative. These are avoided because of the possibility of harm to the fetus.

## Prevention
In developing countries, patients should be advised to consume iron rich foods and fruits and vegetables high in Vitamin C. In babies born to iron deficient mothers, delayed umbilical cord clamping can be helpful in preventing iron deficiency in newborns.
In infants, iron should be supplemented after 6 months of breastfeeding. Iron fortified cereal and formula should be given. Anti helminthic drugs should be given to children with parasitic infections. In areas where prevalence of iron deficiency is high, women of reproductive age group should take daily iron supplements.
References
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