Iron Deficiency Anemia

Iron deficiency anemia is the most common type of anemia worldwide. This form of anemia is caused by insufficient iron due to a decreased supply, an increased loss, or an increased demand. Iron deficiency anemia is seen across all ages, sexes, and socioeconomic strata; however, children, women of childbearing age, and patients from lower socioeconomic strata are at higher risk. Symptoms include pallor, particularly of the mucous membranes, easy fatigability, and headaches. Iron studies are the key to diagnosis. Treatment is based on the underlying cause of iron deficiency and consists of supplementation.

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Overview

Definition

Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview is defined as a hemoglobin level that is 2 standard deviations below the mean for age, sex, and ethnicity. Because iron is a fundamental building block of hemoglobin, a deficiency in this mineral can result in decreased hemoglobin production and anemia.

Epidemiology

  • Most common cause of anemia worldwide (50% of all anemias)
  • More prevalent in developing countries
  • 5%–10% of menstruating women are affected.
  • Infants (6–24 months) consuming cow’s milk have a greater incidence of iron deficiency because consumption of cow’s milk leads to increased GI losses of iron.
  • More common in families with low income/lower socioeconomic status

Etiology

  • Decreased absorption
    • Restricted diets 
      • Vegan/vegetarian diets low in iron
      • Diets rich in dairy (e.g., an infant on cow’s milk)
    • Malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion
      • Insufficient production of gastric acid which normally facilitates iron absorption (e.g., patients on proton pump inhibitor (PPI))
      • Celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease
      • Inflammatory bowel disease
      • After gastrectomy/small bowel resection
  • Increased loss
    • Hemorrhage (e.g., trauma, menorrhagia, cancer, peptic ulcer disease Peptic ulcer disease Peptic ulcer disease (PUD) refers to the full-thickness ulcerations of duodenal or gastric mucosa. The ulcerations form when exposure to acid and digestive enzymes overcomes mucosal defense mechanisms. The most common etiologies include Helicobacter pylori (H. pylori) infection and prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs). Peptic Ulcer Disease)
    • Hemolysis
    • GI parasites 
    • Chronic lower GI bleed 
    • Urinary/pulmonary hemosiderosis
  • Increased demand
    • During pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care, increased demand due to maternal blood volume expansion/fetal needs
    • Treatment with erythropoietin in the setting of CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease
  • Functional deficiency
    • Seen in chronic disease
    • Iron from breakdown of old hemoglobin is not released into circulation by macrophages.
    • Due to chronic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and production of hepcidin

Pathophysiology

  • Iron metabolism is a closely regulated balance of absorption, use, and excretion. 
  • Normal iron needs: 0.5–1 mg/day 
    • Menstruating women: 1–2 mg/day 
    • Pregnant women: 3–5 mg/day
  • Heme synthesis: 
    • Involves combination of ferrous iron (Fe²⁺) with protoporphyrin
    • Decreased bioavailable iron results in deficiency of heme synthesis and oxygen-carrying capacity.
    • Low levels of Fe²⁺ triggers erythropoiesis Erythropoiesis Erythropoiesis starts with hematopoietic stem cells, which develop into lineage-committed progenitors and differentiate into mature RBCs. The process occurs in stages, and extrusion of the nuclei and organelles occurs prior to maturation. Thus, mature RBCs lack nuclei and have a biconcave shape. Erythrocytes and up-regulation of transferrin receptors on RBCs to enhance the delivery of iron to tissues.
  • Stages of iron depletion:
    • Normal iron homeostasis
    • Iron deficiency without anemia:
      • Iron stores are depleted, but sufficient iron is obtained from breakdown of old hemoglobin to make new.
      • No anemia is evident, but individual is vulnerable to it.
    • Iron deficiency with anemia
  • When Fe²⁺ supply decreases, the following processes are affected as well:
    • Ferritin, the storage form of excess iron in the body, decreases.
    • Transferrin, a protein that binds iron in the blood, increases.

Clinical Presentation

Signs and symptoms

  • Pallor
  • Fatigue
  • Shortness of breath
  • Light-headedness
  • Syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope
  • Koilonychia (spoon-shaped, brittle nails)
  • Brittle hair
  • Pica Pica Pica is an eating disorder characterized by a desire or recurrent compulsion to eat substances that are nonnutritive and not food. These compulsions and ingested substances are inappropriate for age or culture. Pica syndrome (craving for nonfood items: dirt, ice, paint, etc.)
  • Restless leg Leg The lower leg, or just "leg" in anatomical terms, is the part of the lower limb between the knee and the ankle joint. The bony structure is composed of the tibia and fibula bones, and the muscles of the leg are grouped into the anterior, lateral, and posterior compartments by extensions of fascia. Leg syndrome
  • Mood disturbances: irritable, shorter attention span

Plummer-Vinson syndrome

  • Dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia: to solids only, due to esophageal webs
  • Glossitis: beefy-red tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue
  • Cheilosis
  • Iron deficiency anemia

Diagnosis

The diagnosis of anemia is clinical, but to qualify it further as iron deficiency anemia, lab testing is necessary.

  • CBC:
    • Hypochromic microcytic anemia
    • ↓ Hb
    • ↓ MCV ( < 70)
    • ↓ MCH (< 25)
    • ↑↑ Red cell distribution width
    • Thrombocytosis: ↑ platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets
  • Iron studies: 
    • ↓ Iron
    • ↓↓ Ferritin
    • ↑↑ Total iron-binding capacity
    • ↑ Transferrin
    • ↓↓ Transferrin saturation
  • Peripheral blood smear
    • Microcytosis and hypochromic RBC
    • Anisocytosis
    • Target cells
    • Pencil cells
  • Bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow aspiration
    • Gold standard (but rarely done)
    • Prussian blue stain: decreased iron in erythroblasts 
  • Find underlying cause: GI workup in men or postmenopausal women
  • 1 of the following findings is necessary for diagnosis:
    • Serum ferritin < 30 ng/mL
    • Transferrin saturation < 19%
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview resolves with iron supplementation.
    • Bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow aspirate without stainable iron
Peripheral blood smear shows hypochromic microcytic cells

Peripheral blood smear shows hypochromic microcytic cells:
Pencil cells and target cells (bull’s-eyes) are also present in this film.

Image: “Peripheral Smear Shows Hypochromic microcytic cells” by Ed Uthman. License: CC BY 2.0

Management

Treat underlying cause

  • Decrease cow’s milk intake in infant. 
  • Suspend interfering medications.
  • Treat inflammatory bowel disease.

Supplementation

  • Oral
    • Ferrous sulfate/ferrous gluconate/ferrous fumarate
    • Duration: 3–6 months
    • Enhance absorption with acidic juice (lowers pH)
  • IM/IV: indicated in those who can’t tolerate oral intake or who have malabsorption
  • Blood transfusion: for severely anemic patient with baseline tachycardia

Response verification

Reticulocytes should increase in 1 week.

Differential Diagnosis

  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview of chronic disease: anemia resulting from chronic illness that presents with entrapment of iron in macrophages or in ferritin. Most commonly seen in chronic renal failure due to lack of erythropoietin production. Total iron-binding capacity is low and hepcidin levels are increased in these cases.
  • Sideroblastic anemia Sideroblastic anemia Sideroblastic anemias are a heterogeneous group of bone marrow disorders characterized by abnormal iron accumulation in the mitochondria of erythroid precursors. The accumulated iron appears as granules in a ringlike distribution around the nucleus, giving rise to the characteristic morphological feature of a ring sideroblast. Sideroblastic Anemia: form of anemia in which iron levels are normal, but iron cannot be incorporated into the heme molecule. Causes of sideroblastic anemia include lead poisoning, vitamin B6 deficiency, and isoniazid. 
  • Thalassemia Thalassemia Thalassemia is a hereditary cause of microcytic hypochromic anemia and results from a deficiency in either the α or β globin chains, resulting in hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present and can range from being asymptomatic to rendering the more severely affected patients to be transfusion dependent. Thalassemia: hereditary hemoglobinopathy that presents with clinical picture similar to that of iron deficiency anemia. However, iron studies are normal in thalassemia and thus iron supplementation can be detrimental.

References

  1. Kassebaum NJ, Jasrasaria R, Naghavi M, Wet al. (2014). A systematic analysis of global anemia burden from 1990 to 2010. https://pubmed.ncbi.nlm.nih.gov/24297872/ 
  2. Centers for Disease Control and Prevention (CDC). (2002). Iron deficiency—United States, 1999–2000. MMWR Morb Mortal Wkly Rep. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5140a1.htm
  3. Cook JD, Skikne BS. (1989). Iron deficiency: definition and diagnosis. J Intern Med. https://pubmed.ncbi.nlm.nih.gov/2681511/ 
  4. Annibale B, Capurso G, Chistolini A, D’Ambra G, DiGiulio E, Monarca B, DelleFave G. (2001). Gastrointestinal causes of refractory iron deficiency anemia in patients without gastrointestinal symptoms. Am J Med. https://pubmed.ncbi.nlm.nih.gov/11690568/ 
  5. Lopez A, Cacoub P, Macdougall IC, Peyrin-Biroulet L. (2016). Iron deficiency anaemia. Lancet. https://pubmed.ncbi.nlm.nih.gov/26314490/

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