Iron Deficiency Anemia: Causes, Lab Diagnosis and Treatment

Iron deficiency anemia is a type of anemia which occurs when the body does not have enough iron to produce the hemoglobin it needs.

Functions and Metabolism of Iron

Iron is present in all cells in the human body. It performs several vital functions including:

• Carrying oxygen to the tissues from the lungs in the form of hemoglobin. Hemoglobin binds to oxygen, enabling red blood cells to supply oxygenated blood throughout the body.
• Acting as a transport medium for electrons within the cells in the form of cytochromes.
• Facilitating oxygen enzyme reactions in various tissues.

Deficiency of iron can interfere with these important functions and lead to morbidity and even death in extreme cases.

Total body iron of normal adult varies from 3 to 5 g depending on sex and weight of the person. It is greater in males than in females.

Distribution

It is distributed in the body in the following forms

Hemoglobin iron

It constitutes 60-70% of total body iron.
The iron released by the breakdown of hemoglobin is released into the circulation bound to iron-binding protein, transferrin and is re-utilized by the bone marrow for hemoglobin synthesis.

Tissue iron

It is divided into two types.

Storage or available iron which can be mobilized for hemoglobin synthesis. It includes ferritin and hemosiderin.

Non-available tissue iron is not available for hemoglobin synthesis and includes myoglobin and enzymes of cellular respiration such as cytochrome, etc.

Plasma or transport iron

Around 3-4 mg of iron is present in the plasma which is attached to a specific protein-transferrin. The function of transferrin is the transport of iron. After absorption from the intestine, iron is transported to tissue stores, bone marrow and from one storage site to another through transferrin.

Absorption

Regulation of iron absorption is the chief mechanism by which the body controls its iron levels since the ability of the body to excrete iron is very limited. The small intestine is highly sensitive to changes in iron stores and increases or decreases the absorption depending upon the iron levels in the body.

Prevalence and Etiology of Iron Deficiency Anemia

Iron deficiency anemia is a global health problem and the most common type of anemia.
About 20% of the world’s population is estimated to have varying degrees of iron deficiency. It involves people of all age groups.

It is more prevalent in developing and underdeveloped countries and people of low socio-economic status due to poor dietary intake. In developed countries, chronic and occult blood loss is the major contributing factor.

It is more common in females than in males. Adolescent girls and women of child-bearing age show a high prevalence due to increased metabolic demand and increased blood loss.
It is also very commonly seen in infants and children due to a deficient diet and diminished iron stores at birth. About 15% of children in the age group of 1-3 years suffer from iron deficiency anemia.

Causes of Iron Deficiency Anemia

Inadequate Intake of Iron

Inadequate iron intake due to poor diet is the leading cause of iron deficiency. Thus it is more commonly seen in people of low-socio-economic status.

Increased Demand of Iron

Increased demand for iron due to menstruation, pregnancy or repeated miscarriages deplete a woman’s iron stores and results in the highest incidence of iron deficiency in teenage girls and women of reproductive age group.
An iron-poor diet, especially in infants, children, and teenagers which fails to meet the increased demands of growth results in iron deficiency anemia.

Chronic Blood Loss

Menstrual blood loss

Menstruation especially heavy periods puts females at a higher risk for iron deficiency. Excessive blood loss due to either uterine fibroids, uterine polyps or cancer of female genital tract can also be the causative factors.

Gastrointestinal blood loss

The following diseases affecting the gastrointestinal tract lead to blood loss:

• Esophageal varices
• Peptic ulcer
• Hemorrhoids
• Hiatus hernia
• Chronic aspirin ingestion
• Ulcerative colitis
• Intestinal parasitic infestation
• Carcinomas of stomach or colon

Other causes of chronic blood loss

• Epistaxis (bleeding from nose)
• Hematuria (blood in urine due to diseases of kidney or urinary bladder)
• Hemoptysis (blood in sputum due to disaeases of respiratory system)

Decreased Ability to Absorb Iron

Iron from food is absorbed into the bloodstream through the small intestine. Any intestinal disorder which affects the intestine’s ability to absorb nutrients from digested food can lead to iron deficiency. These include

• Celiac disease
• Inflammatory bowel disease
• Surgical removal of part of the small intestine

Clinical Features

Symptoms

Mild anemias may get unnoticed. Common symptoms of anemia include:

• Weakness, fatigue, and general malaise
• Diminished capability to perform hard labor
• Shortness of breath
• Leg cramps on climbing stairs
• Pica, the consumption of non-food items such as dirt, ice, mud, paper, wax, grass, etc., may be seen in some patients.
• Chronic anemia may result in behavioral disturbances in children, poor concentration and poor scholastic performance in school going children.
• Reduced resistance to infection
• Headache and dizziness
• Hearing sounds that come from inside the body, rather than from an outside source (tinnitus)
• Poor appetite
• Dysphagia with solid foods (due to esophageal webbing) Plummer–Vinson syndrome
• Restless leg syndrome
• In very severe anemia, the body may compensate for the lack of oxygen-carrying capability of the blood by increasing cardiac output. The patient may then have symptoms such as palpitations, angina, and heart failure.

Signs

• Pallor of skin, conjunctiva and nail beds
• Impaired growth in infants
• Spoon-shaped nails (koilonychia)
• A glossy, smooth tongue, with atrophy of the lingual papillae
• Fissures at the corners of the mouth (angular stomatitis)
• Splenomegaly (in severe, persistent, untreated cases)
• Pseudotumor cerebri (a rare finding in severe cases)

Diagnosis

Complete Blood Count

It shows reduced hemoglobin levels of varying degrees. Hematocrit is also reduced.
Mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) are reduced to varying degrees depending on the severity of anemia.
WBC count and differential are usually normal.
Platelet count is usually normal but may be slight to moderately increased, especially in patients who are bleeding.

Reticulocyte Count

It is reduced in iron deficiency anemia because the bone marrow is producing less of erythrocytes.

ESR

It is raised depending upon the degree of anemia.

Peripheral Blood Smear

Iron deficiency results in microcytic hypochromic anemia which means that the red blood cells are smaller and paler in color than normal.
Red cells may exhibit anisocytosis and poikilocytosis.
Elliptical cells, pencil-shaped cells, and target cells may be seen in variable numbers.
However, in contrast with thalassemia (which also presents with microcytic hypochromic blood picture), target cells are usually not present in large numbers.

Iron Studies

Levels of serum iron, serum ferritin, and transferrin saturation are reduced while TIBC is increased in iron deficiency anemia.

Serum iron

Normal serum iron level: 10 to 30 µmol/L

Levels less than 10 µmol/L are seen in iron deficiency anemia.

Total iron-binding capacity (TIBC)

In iron deficiency anemia, TIBC is increased sometimes up to 100 µmol/L or even more.

Transferrin saturation

It is decreased to below 16% in iron deficiency anemia.

Serum ferritin

Ferritin protein helps store iron in the body. Normal levels of ferritin: 40 to 300 µg/l for men and 20 to 200 µg/l for women.
Levels less than 10 µg/l indicate a low level of stored iron and hence iron deficiency anemia.
Ferritin is also an acute phase reactant and is elevated in inflammation, infection, liver disease and malignancy. This can potentially lead to misleading results in patients who are iron deficient with co-existing systemic illness.

Red Cell Protoporphyrin

It is increased in iron deficiency. Protoporphyrin accumulates in red cells in the free form as there is insufficient iron to combine with it to produce haem.

Tests to Evaluate Hemosiderinuria, Hemoglobinuria, and Pulmonary Hemosiderosis

Bone Marrow Examination

It is not required for diagnosis and is not routinely performed in suspected iron deficiency. Bone marrow shows erythroid hyperplasia with an increase in more mature forms (polychromatic normoblasts). There is micronormoblastic erythropoiesis that is the erythroid precursors are smaller in size. The cytoplasm is scanty with a ragged border. Cytoplasmic maturation lags behind nuclear maturation, so nucleus often appears small and pyknotic while the cytoplasm is still polychromatic.
Granulopoietic cells and megakaryocytes are normal in number and morphology.
Bone marrow aspiration and trephine biopsies when stained with potassium ferrocyanide (Perl’s Prussian blue stain) show the absence of reticuloendothelial iron and reduction in sideroblasts.

Hemoglobin Electrophoresis

This test is done to rule out thalassemia minor or other hemoglobinopathies which also present with anemia and a microcytic hypochromic blood picture. Levels of hemoglobin A2 and/or fetal hemoglobin are raised in thalassemia while they are normal in iron deficiency anemia.

To see if iron-deficiency anemia is due to gastrointestinal bleeding, the following procedures or tests may be carried out:

Stool Examination

To look for eggs or cysts of intestinal parasites.

Fecal Occult Blood Test

To check for the presence of blood in the stool. Blood in stool would suggest bleeding in the gastrointestinal tract and may require further testing.

Endoscopy

In this procedure, a thin, lighted tube equipped with a video camera is passed down the throat up to the stomach. It helps to visualize the upper gastrointestinal tract to look for any hiatal hernia or ulcer which could be a source of bleeding.

Colonoscopy

In this procedure, a thin, flexible tube equipped with a video camera is inserted into the rectum and guided up to the colon. It helps to visualize the lower gastrointestinal tract to rule out the presence of polyps, cancerous growth or any other cause of internal bleeding.

Ultrasound

Females may be advised a pelvic ultrasound to look for causes of excessive menstrual bleeding, such as uterine fibroids, polyps, etc.

Treatment

Treatment of The Underlying Disorder

Any abnormal cause of bleeding or chronic blood loss needs to be investigated and treated. If the patient has heavy menstrual blood flow, the underlying cause needs to be appropriately treated. For a patient suspected of having gastrointestinal bleed, thorough investigations should be instituted to find the actual cause.

Increased Dietary Iron Intake

The patient should be encouraged to take iron-rich foods. Good dietary sources of iron include red meat, beans, egg yolk, whole-grain products, nuts, seafood, jaggery, green leafy vegetables, etc. Many processed foods and milk are also fortified with iron.

Oral Iron Administration

Oral iron administration is the first line of treatment. Ferrous iron salts, (most commonly ferrous sulfate) are used.

To increase the absorption of iron, tea and coffee should be avoided. The patient should also be instructed to take orange juice or vitamin C (500 units) along with iron medication once daily. This helps to increase the bioavailability of iron and results in better absorption.

Oral iron therapy is effective when intestinal uptake is intact. Also, it is beneficial only in cases of mild anemia because repletion occurs slowly. When anemia is severe and quick repletion is required, parenteral administration and/or blood transfusion should be preferred. Diminished patient compliance due to side effects also limits the efficacy of oral iron.

Oral therapy has the advantage of being non-invasive, easily available, inexpensive, and convenient, making it the first line of treatment in the majority of the patients.
An increase of 2 g/dl of hemoglobin after 4-8 weeks of oral therapy suggests success of the therapy. If there is no response, alternative treatment should be considered along with an assessment of the cause of the lack of response.
Depending on the severity of anemia and underlying cause, it may take up to 3 months for Hb level to return to normal values and it may take even longer to replace the depleted iron stores.

Parenteral Iron Administration

Intravenous and intramuscular iron preparations are reserved for patients who are either unable to absorb oral iron or who have increasing anemia despite adequate doses of oral iron.
It is expensive, requires the services of a healthcare professional and has greater morbidity than oral therapy.

Blood Transfusion

It is given in extreme cases to help replace iron and hemoglobin quickly.

Following are its indications:

• Chronic iron deficiency anemia
• Patients with active bleeding who are hemodynamically unstable
• Patients with severe anemia (Hb level <6 g/dL)
• In case of failure of oral and parenteral treatment

Transfusions are only a temporary and quick-fix solution. For proper management, the underlying condition should be investigated and treated. Also, intravenous iron (and erythropoiesis-stimulating agents, if necessary) should be given along with blood transfusion to maintain the Hb level and replenish iron stores. This also reduces the need for subsequent transfusions.