Microcytic Anemia and Hemoglobin Synthesis

Microcytosis = when MCV is 79 fL and the RBC are microcytic (and hypochromic)

We will look at the five (5) main causes of microcytosis. We start out by discussing the structure of haemoglobin (Hb) and where and how it is synthesised during RBC development.

We differentiate the causes of microcytosis into:

1) reduced/absent or defective haem synthesis

2) reduced/absent globin chain synthesis.

For the remainder we go through each condition and discuss the pathophysiology, expected FBC, blood film morphology and additional tests used to diagnose them. While we focus mostly on iron deficiency anaemia and anaemia of chronic disease (they are the most common), we still need to know what lead poisoning and congenital sideroblastic anaemia are so study those as well. At the end, we have a brief introduction to thalassaemia (and will learn that next as separate topic). As such, your learning objectives are:

  1. Describe the pathophysiology of:

    1. Iron deficiency anaemia (IDA)

    2. Anaemia of chronic disease (ACD) - reminder, almost all cases are normocytic normochromic

    3. Lead poisoning

    4. Congenital sideroblastic anaemia

    5. ...save thalassaemia for next week

  2. List the expected FBC and morphology for each condition.

  3. List the tests (and expected results) used to investigate and confirm/diagnose them.

    1. Note, for the tests performed in Chem Path (i.e., iron studies), you don't have to describe the principle in detail e.g., chemical reactions etc. You will be assessed on that in LSB525. For LSB555, just make sure, you know what each analyte is and when/what it used to measure, e.g., what is ferritin (or TS%, TIBC, Fe, TfR) and when/why it is measured (or the test requested)?

  4. Describe and explain iron regulation and metabolism (use diagrams to help do this).

  5. Explain how and where Hb is synthesised, as well its final structure (use diagrams to help do this).

Introduction to Microcytosis

  • Microcytosis is defined as the condition where red blood cells are smaller than normal.

  • Key parameter used to determine microcytosis is mean cell volume (MCV), which is the average size of red blood cells.

Classification of Red Blood Cell Sizes

  • Red blood cells can be classified into three categories based on MCV:

    • Microcytic: MCV ≤ 79 fL

    • Normocytic: MCV is between 80-100 fL

    • Macrocytic: MCV ≥ 100 fL

Visual Representation of Red Blood Cells

  • The presentation includes images of microcytic and macrocytic red blood cells alongside a small lymphocyte used for size comparison.

  • Microcytic red blood cells appear smaller and have reduced hemoglobinization, a light pink rim around the edge.

  • Macrocytic red blood cells appear larger than the lymphocyte nucleus and have a more normal staining pattern, possibly darker.

Microcytic Conditions

  • The focus will be on microcytic conditions that affect hemoglobin and red blood cell production:

    • Iron deficiency anemia

    • Anemia of chronic disease

    • Lead poisoning

    • Congenital sideroblastic anemia

    • Thalassemia

Hemoglobin Structure and Synthesis

  • Hemoglobin consists of four globin chains, each associated with a heme molecule containing iron which is crucial for oxygen transport in the body.

  • Hemoglobin is synthesized during red blood cell development, primarily in the bone marrow, but also in circulating red blood cells while they possess a nucleus.

  • Iron enters the cell through transferrin receptors and can be stored as ferritin or used in mitochondria for heme production.

Hemoglobin Composition

  • Hemoglobin is composed of two alpha globin chains and two beta globin chains.

  • Disorders affecting heme synthesis lead to diminished hemoglobin synthesis resulting in microcytosis.

  • Disorders can be categorized:

    • Reduced or defective heme synthesis linked to conditions like iron deficiency, lead poisoning, and anemia of chronic disease.

    • Reduced globin chain synthesis linked to thalassemia.

Anemia of Chronic Disease

  • Typically starts as normocytic, normochromic and can progress to microcytic, hypochromic.

  • Caused by inflammatory cytokines (especially interleukin 6) that increase hepcidin levels, which decreases iron availability by trapping it in macrophages and hepatocytes.

  • Serum ferritin levels may be normal or increased, which differentiates it from iron deficiency anemia.

Iron Deficiency Anemia

  • The most prevalent form of anemia, especially in women of childbearing age.

  • Causes: inadequate dietary intake, poor absorption, or increased demand/loss of iron (e.g. blood loss).

  • Leads to decreased heme synthesis, reduced hemoglobin, and smaller, paler red cells with hypochromia and microcytosis.

  • Symptoms include fatigue, shortness of breath, and potential heart-related impacts.

Body Iron Stores and Absorption

  • Iron exists in three main forms in the body:

    • Functional iron: predominantly in hemoglobin, accounting for about 75% of total body iron.

    • Storage iron: primarily ferritin (majority), and hemosiderin (less accessible for mobilization).

    • Transport iron: primarily transferrin which carries iron throughout the body.

  • Daily iron requirements vary, usually highest in menstruating women (around 18 mg/day).

Regulation of Iron Levels

  • Hepcidin is a key hormone regulating iron homeostasis; high levels restrict iron absorption and release.

  • Low hepcidin levels increase iron absorption via ferroportin and transferrin receptors, promoting erythropoiesis.

Symptoms and Assessment of Iron Deficiency

  • Diagnostic indicators of iron deficiency include low ferritin, low serum iron, high total iron binding capacity, and decreased transferrin saturation.

  • Blood films will reveal microcytic, hypochromic cells, elliptocytes, and increased RDW as a sign of varying cell sizes.

Types of Microcytic Anemia

  • Lead Poisoning:

    • Interferes with heme synthesis by competing for enzymes.

    • Characterized by basophilic stippling in blood cells, Pappenheimer bodies, and potentially hemolysis.

  • Congenital Sideroblastic Anemia:

    • Rare, often X-linked, and linked to an enzyme defect in mitochondrial synthesis of erythropoietin.

    • Characterized by ring sideroblasts and basophilic stippling in blood films.

Thalassemia Overview

  • A hereditary disorder affecting globin chain synthesis leading to reduced production of either alpha or beta chains; results in microcytosis.

  • Thalassemia is the most common genetic blood disorder worldwide.

  • Characterized by a normal or increased red blood cell count, differentiating it from iron deficiency anemia.

Key Diagnostic Features

  • To differentiate various forms of anemia:

    • Iron deficiency: Low ferritin, microcytic cells (elliptocytes, pencil cells).

    • Anemia of chronic disease: Normal/increased ferritin levels.

    • Thalassemia: Normal/increased red blood cell count with distinct morphological features in blood films.

    • Lead poisoning and congenital sideroblastic anemia: Presence of stippling and unique patterns in red blood cells based on environmental exposure or genetic factors.