Unit_4-Lecture_1-Iron_Metabolism_and_hyp_anemias.

Hematology I: Iron Metabolism and Hypochromic Anemias

Unit Overview

Focused on the complex processes of iron metabolism and the pathogenesis of various hypochromic anemias. This unit extensively covers chapters 8 and 17, providing a comprehensive understanding of how iron deficiency and related disorders affect hematological health.

Learning Objectives

• List components of hemoglobin: Gain an understanding of how hemoglobin is structured, including the four heme groups and globin chains, focusing on the importance of iron in maintaining its functionality.

• Discuss the function and importance of iron in hemoglobin structure: Explore how iron plays a crucial role in oxygen transport and the biochemical reactions essential for cellular respiration.

• Diagram the transport of iron from ingestion to incorporation into heme: Visualize and understand the mechanisms involved in iron absorption, transport proteins such as transferrin, and the utilization of iron in the synthesis of hemoglobin.

• Define key terms related to iron metabolism: Master the terminology associated with iron metabolism, including transferrin, hemosiderin, ferritin, Total Iron Binding Capacity (TIBC), Hepcidin, Hemojuvelin, and the Hemochromatosis Gene.

• Describe physiological factors affecting body iron requirements: Analyze how factors such as age, sex, diet, and physiological state (e.g., pregnancy, growth spurts) influence individual iron needs.

• List three stages of iron deficiency and compare related laboratory findings in various types of anemia, including microcytic and normocytic presentations.

Introduction to Anemias

Hypochromic anemias, particularly microcytic anemias, arise due to defects in hemoglobin synthesis. Key types include:

1. Iron-Deficiency Anemia (IDA): Most prevalent type of anemia resulting from inadequate iron supply.

2. Anemia of Chronic Disease (ACD): Often accompanies chronic infections or malignancies, leading to altered iron metabolism.

3. Sideroblastic Anemia: Characterized by abnormal hemoglobin synthesis due to defects in heme production.

4. Thalassemia: genetic blood disorder marked by diminished production of globin chains in hemoglobin, leading to anemia and ineffective erythropoiesis. It can be classified into alpha thalassemia and beta thalassemia, with severity varying based on the affected globin chains.

The normal heme molecule comprises iron, globin, and protoporphyrin. In adults, the composition is represented by four heme groups and four globin chains (2α + 2β chains). Defective hemoglobin production can result from:

• Heme synthesis issues due to genetic mutations.

• Iron deficiencies reducing the availability of essential components.

• Various metabolic defects impacting red blood cell maturation.

Iron in the Body

Two Categories of Iron:

• Heme Iron: Incorporated into hemoglobin and certain enzymes, crucial for oxygen transport. It is primarily derived from animal sources and is more easily absorbed by the body.

• Non-Heme Iron: Present in plant sources and supplements. Transfer and storage compounds are essential for iron homeostasis:

  • Transferrin: A glycoprotein that binds iron and transports it to various tissues.

  • Ferritin: The primary storage form of iron; it is soluble and can quickly release iron when required.

  • Hemosiderin: An insoluble form of stored iron, typically derived from the breakdown of ferritin, and less readily available for use.

Iron Metabolism Basics

Iron Requirements:

An estimated 20-25 mg of iron is required daily. As approximately 1% of total red blood cells are lost each day, iron recycling is crucial to maintain adequate levels. Dietary sources include:

• High: Organ meats, wheat germ, legumes.

• Moderate: Muscle meats, fish, and a variety of vegetables.

Iron Absorption

Key Factors Influencing Absorption:

Factors that significantly affect iron absorption include:

• Type of iron: Heme iron is better absorbed than non-heme iron.

• Gastrointestinal health: Conditions such as celiac disease or inflammatory bowel disease can impair absorption.

• Current iron stores: High iron levels in the body can restrict absorption.

• Body’s erythropoietic needs: Increased demand during periods of rapid growth or recovery from anemia enhances absorption.

Increased Absorption:

Occurs with:

• Ferrous state iron (Fe2+).

• Presence of acidic foods or Vitamin C, which markedly enhances iron solubility in the intestine.

Decreased Absorption:

Hindered by:

• Ferric state iron (Fe3+).

• Compounds like phytates and large amounts of antacids which interfere with iron bioavailability.

Regulation of Iron Absorption

Hepcidin: A key hormone secreted by the liver, regulates iron absorption by binding to ferroportin, leading to the decreased release of iron into the circulation when the body’s iron stores are high.

Current Stores: Iron levels can be indirectly measured through ferritin concentration in serum. Efficient iron absorption occurs primarily in the duodenum, requiring iron to be in a ferrous state for optimal transport across enterocytes.

Iron Storage

Forms of Iron Storage:

• Ferritin: Serves as the primary long-term storage form, readily available for erythropoiesis, and is predominantly located in the bone marrow, liver, and spleen.

• Hemosiderin: A byproduct of ferritin degradation, it represents an excess iron reserve that is less bioavailable and more stable.

Iron Balance

To maintain homeostasis, daily iron absorption must match the amount of iron lost, typically around 1 mg/day. Conditions that affect this delicate balance include:

• Insufficient dietary intake.

• Impaired absorption due to gastrointestinal disorders.

• Increased iron loss through menstruation or bleeding.

• Overload scenarios from excessive intake or disorders of iron metabolism.

Clinical Implications of Iron Deficiency Anemia (IDA)

Signs and Symptoms:

Commonly include:

• Pallor and fatigue as tissues become oxygen-deprived.

• Increased irritability, particularly in populations such as children.

• Cardiovascular alterations, such as tachycardia and elevated heartbeat in response to low oxygen levels.

Laboratory Features:

Characterized by:

• Microcytic hypochromic anemia seen on complete blood count (CBC).

• Low serum iron indicating deficiency.

• High TIBC, suggestive of enhanced iron transport demand.

• Low ferritin levels, indicating depleted iron stores.

Pathophysiology of IDA

IDA progresses through three distinct stages:

1. Stage I: Iron depletion characterized by decreased ferritin levels without anemia.

2. Stage II: Iron deficient erythropoiesis with possible mild microcytosis.

3. Stage III: IDA, marked by a significant drop in hemoglobin, leading to clear clinical symptoms.

Anemia of Chronic Disease (ACD)

Features:

Often associated with chronic diseases, resulting in low serum iron due to sequestration, while ferritin may remain normal or elevated. TIBC generally decreases due to reduced iron turnover.

Laboratory Findings:

Typically, ACD presents as normocytic unless prolonged, with laboratory values usually milder compared to IDA.

Sideroblastic Anemias

Characterized by defects in heme synthesis, resulting in ineffective erythropoiesis and iron accumulation within the marrow.

Lab Features:

Presence of dimorphic erythrocytes and signs of iron overload in laboratory assessments, including ringed sideroblasts visible in bone marrow examinations.

Hemochromatosis

This clinical disorder is marked by excessive iron accumulation, leading to damage to parenchymal tissues. Symptoms often include:

• Fatigue and substantial joint pain (arthralgia).

• Complications like diabetes mellitus due to pancreatic damage. Careful monitoring and management strategies are necessary, which might include therapeutic phlebotomy or iron chelation therapy to reduce iron overload.

Laboratory Assessment of Iron

A thorough evaluation includes:

• Complete blood count (CBC), serum iron assays, TIBC assessments, and ferritin levels to diagnose the specific type of anemia accurately.

• Bone marrow examination may be indicated if initial tests reveal abnormal erythropoiesis, particularly to differentiate sideroblastic anemia from other forms.