Disorders of Iron Metabolism and Heme Synthesis

Chapter 14: Disorders of Iron Metabolism and Heme Synthesis

Iron Deficiency Anemia and Iron Overload

  • Iron Deficiency Anemia (IDA)
    • Causes of IDA:
    • Absolute Iron Deficiency: Represents a decrease in total body iron, potentially due to:
      • Blood loss
      • Decreased dietary intake of iron
      • Increased utilization of iron
    • Functional Iron Deficiency: Represents inadequate utilization of existing iron stores, associated with:
      • Iron sequestration syndromes, e.g., Anemia of Chronic Disease (ACD)/Anemia of Inflammation (ACI).
  • Iron Overload: Can be caused by:
    • Inherited alterations in iron uptake and retention
    • Chronic disorders such as sideroblastic anemia
    • Iron therapy or blood transfusions
    • Hemolytic anemias
    • Hereditary hemochromatosis (HH)

Early Diagnosis

  • Timely diagnosis of iron deficiency is critical for:
    • Nonanemic infants and toddlers (especially under 2 years of age)
    • Pregnant women to mitigate maternal-fetal morbidity

Factors in Iron Deficiency Anemia

  • Contributing Elements:
    • Excessive Loss:
    • Pathological (e.g., overt bleeding)
    • Physiological (e.g., menstrual loss)
    • Nutritional Deficiency: Lack of dietary iron
    • Increased Physiological Demand: Situations necessitating higher iron intake (e.g., growth spurts, pregnancy)
    • Faulty or Incomplete Absorption: Issues stemming from gastrointestinal conditions, e.g., celiac disease, bowel resection

Etiology

  • Decreased Iron Intake: Common in diets low in meat
  • Faulty or Incomplete Iron Absorption: Conditions affecting absorption capabilities
  • Increased Iron Utilization: We see this during times of growth spurts
  • Iron Loss:
    • Pathological Iron Loss: Associated with conditions like gastrointestinal bleeding, malignancy
    • Physiological Iron Loss: Normal body processes, e.g., pregnancy or menstruation

Pathophysiology of IDA

  • Sequential Phases of Iron Deficiency:
    • Stage 1 (Prelatent):
    • Decrease in storage iron, with reduced levels of ferritin
    • Stage 2 (Latent):
    • Decrease in functional and circulating iron for erythropoiesis
    • Indicators:
      • Decreased serum iron
      • Increased Total Iron-Binding Capacity (TIBC)/Unsaturated Iron-Binding Capacity (UIBC)
    • Stage 3 (Anemia):
    • Decrease in circulating red blood cell parameters (RBC, hemoglobin, hematocrit)
    • Compromised oxygen delivery to peripheral tissues

Laboratory Characteristics

  • Hematology:

    • IDA results shift with disease progression:
    • Mean Corpuscular Volume (MCV): Initially normocytic, progresses to microcytic
    • Mean Corpuscular Hemoglobin Concentration (MCHC): Initially normochromic, later hypochromic
    • Reticulocyte Count: Often stable (low or normal) due to ineffective erythropoiesis
    • Initial stages might show normal RBC, hemoglobin (H&H), but may decrease in later stages
    • Platelet and white blood cell counts may elevate owing to Erythropoietin (EPO) and Thrombopoietin (TPO) homology.

  • Iron Deficiency Anemia Characteristics:

    • Ineffective erythropoiesis impacts both red blood cell production and hemoglobin synthesis
    • A reticulocyte count < 2.5% aids in categorizing other forms of anemia
    • Reticulocyte Hemoglobin Content (CHr): Early indicator of iron deficiency
    • Importance of early detection in infants and toddlers due to risks of cognitive and psychomotor developmental issues.

Clinical Chemistry Studies

  • Important Metrics:
    • Serum Iron: Measures iron bound to transferrin
    • Transferrin Saturation: Percentage of transferrin occupied by iron
    • Serum Ferritin: Reflects storage iron
    • Soluble Transferrin Receptor (sTfR): Indicates soluble transferrin receptor concentration

Comparative Laboratory Findings

Table 14.4: Iron Studies
  • Conditions: Fe Def Without Anemia, Fe Def With Mild Anemia, Fe Def With Severe Anemia
    • Marrow Iron Stores:
    • (+) for normal, (0) for deficiency categories
    • Serum Iron Level: Normal or decreased (N/↓) across anemia categories
    • Hemoglobin: Normal (N), slight decrease (Slight ↓), microcytic (Microcytic)
    • Ferritin: Decreasing in all categories
    • Free RBC Protoporphyrin Level (FEP): Normal or increased (Nor↑), decreased in deficiency cases
IDA versus ACD/AI
Table 14.6: Comparison of Classic IDA versus ACD
  • Conditions: Serum Iron, TIBC, Serum Ferritin, Transferrin, sTfR, Transferrin Saturation, Peripheral Blood morphology and characteristics

Subsequent Laboratory Characteristics

  • Hypercellular Bone Marrow: Typically presenting with normal reticulocyte count
  • Mature RBCs: Generally hypochromic with normocytic/microcytic features
  • Notable Cytological Findings: Presence of basophilic stippling and/or Pappenheimer bodies

Chapter 15: Macrocytic and Megaloblastic Anemias

Macrocytic Anemias

  • Definition: Macrocytosis signifies increases in MCV, commonly ranging from 100 to 120 fL.
  • Differentiation: Megaloblastic anemias exhibit this phenomenon, but macrocytosis may arise from other non-megaloblastic etiologies.

Megaloblastic Anemias

  • Characteristic Features:
    • Hypercellular marrow with nuclear-cytoplasmic asynchrony
    • Presence of intramedullary cell death due to ineffective erythropoiesis
    • Clinical observations of leukopenia and thrombocytopenia
    • Categories:
    • Vitamin B12 (Cobalamin) deficiency
    • Folic acid deficiency

Etiological Factors of Megaloblastic Anemias

  • Increased B12 utilization based on:
    • Parasitic infections (e.g., Diphyllobothrium latum)
    • Pathogenic bacterial growth (e.g., diverticulitis)
    • Malabsorption syndromes:
    • Caused by gastric resections, malignancies, celiac disease
    • Inflammatory conditions targeting the terminal ileum
    • Direct nutritional deficiencies

Pernicious Anemia (PA)

Etiology of PA
  • Often associated with autoimmune endocrinopathies:
    • Chronic autoimmune thyroiditis (Hashimoto’s)
    • Insulin-dependent diabetes mellitus
    • Addison’s disease
    • Primary ovarian failure, primary hypoparathyroidism
    • Graves’ disease, myasthenia gravis
Epidemiology of PA
  • Prevalence: 1.9% of individuals over 60 years may have undiagnosed PA.
  • Historical beliefs suggested PA was primarily in Northern Europeans; however, recent research indicates cases in diverse populations (Blacks and Latin Americans).
  • Typical age of diagnosis is around 60 years, with a slightly higher incidence among women.

Physiology Related to Anemia

  • Folate: Crucial for synthesizing thymidine nucleotides used for DNA synthesis:
    • Tetrahydrofolate donates methyl groups to dUMP for thymidine formation.
  • Vitamin B12: Serves as a source for folate; removes methyl groups and converts homocysteine to methionine.

Clinical Signs and Symptoms of PA

  • Changes in skin color, possibly presenting as lemon-yellow appearance, along with:
    • Hyperpigmentation in certain areas (nail beds, skin creases, periorbital)
    • Symptoms: Angular cheilitis, dyspepsia, diarrhea, glossitis, painful tongue
    • General fatigue, shortness of breath (dyspnea), vertigo, tinnitus due to anemia
    • Potential heart complications: Congestive heart failure, angina, palpitations
    • Neurological and cognitive disturbances

Laboratory Findings Related to PA

  • Common abnormalities include low hemoglobin levels, low microhematocrit, and low RBC count.
  • Mean Corpuscular Volume (MCV): High values, potentially reaching 130 fL.
  • Mean Corpuscular Hemoglobin (MCH): Varies but is increased in 90% of cases.
Megaloblastic Anemia Testing
Table 15.2: Testing Parameters
  • Basic Testing Levels for Vitamin B12 and Folate
  • Follow-Up: Serum methylmalonic acid (MMA) and homocysteine levels as confirmatory measures.

Clinical Chemistry in Megaloblastic Anemias

  • Key Indicators:
    • Serum haptoglobin-binding capacity: generally decreased
    • Decreased serum vitamin B12
    • Normal folate levels
    • Increased serum iron
    • Normal or decreased total iron-binding capacity
    • Elevated serum lactic dehydrogenase (LDH) isoenzymes 1 and 2
    • Increased unconjugated bilirubin
    • Elevated urinary methylmalonic acid and homocysteine levels

Folic Acid Deficiency

Etiology of Folic Acid Deficiency
  • Potential drug interactions possibly causing absorption issues
  • Increased physiological demands (e.g., pregnancy or acute leukemia)
  • Treatment with folate antagonists like antimetabolites
Sources and Storage of Folate
  • Dietary sources include yeast, green leafy vegetables, and organ meats (liver and kidneys).
  • Human body does not retain substantial stores, generally capable of about a 3 to 4 month supply.
  • Chronic deficiency may lead to megaloblastic anemia; alcohol listed as significant factor affecting folate levels.
Epidemiology of Folic Acid Deficiency
  • Key contributing factors include:
    • Low dietary intake of folic acid (green leafy vegetables)
    • Increased requirements during pregnancy and infancy
    • Conditions leading to malabsorption (e.g., sprue, gluten sensitivity)
    • Intestinal bacterial overgrowth competing for dietary folate
    • Influence of medications, alcoholism, etc.

Chapter 16: Hemolytic Anemias

Overview of Hemolytic Anemia (HA)

  • Commonality among hemolytic anemias includes the premature destruction of erythrocytes
    • Primarily occurs through:
    • Trapping within the sinuses of the spleen or liver (extravascular destruction)
    • In blood vessels (intravascular destruction)
  • Intrinsic Causes: E.g., hemoglobinopathies, RBC membrane defects, enzyme defects
  • Extrinsic Causes: Includes vascular defects, antibody-mediated processes, infectious agents, toxins, and mechanical devices

Classification of Hemolytic Anemia

  • Additional organization of hemolytic anemias includes:
    • Inherited vs. Acquired
    • Intravascular vs. Extravascular
    • Immune vs. Non-immune
  • Increased bone marrow (BM) activity may compensate for RBC loss; nevertheless, anemia develops if BM fails to enhance production.
  • Hemolysis can be asymptomatic or present life-threatening challenges.

Hemolytic Anemia: Membrane Disruption

  • Can be classified into:
    • Inherited Disorders (intrinsic hemolytic anemia)
    • Acquired Disorders (extrinsic hemolytic anemia)
    • Further subdivided based on causative mechanisms: Site of destruction (intravascular versus extravascular)

Comparison of Intravascular versus Extravascular Hemolysis

Table 16.1: Comparison Metrics
  • Site of Destruction: Locations vary between within blood vessels (intravascular) and in spleen/liver (extravascular)
  • Mechanism: Activation of complement with immunoglobulin distinctions; laboratory findings help differentiate

Specific Types of Hemolytic Anemias

  • Hereditary Spherocytosis
  • Hereditary Elliptocytosis
  • Hereditary Stomatocytosis
  • Acanthocytosis

Erythrocytic Enzyme Defects

  • Disorders affecting RBC metabolism classified under congenital nonspherocytic hemolytic anemias (CNSHA) include:
    • Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
    • Pyruvate Kinase Deficiency
    • Methemoglobin Reductase Defects
  • Clinical presentations vary significantly in terms of severity.

Acquired Hemolytic Anemia

Associated Microorganisms
Table 16.2: Representative Pathogens
  • Bacteria: Bartonella bacilliformis, Neisseria meningitidis, Mycobacterium tuberculosis among others
  • Parasites: Examples include Plasmodium falciparum, Babesia species
  • Viruses: Cytomegalovirus, Epstein-Barr Virus

Mechanisms of Immune Hemolytic Anemia

Classification
Box 16.4: Types of Autoimmune and Isoimmune Hemolytic Anemias
  • Autoimmune Hemolytic Anemias:
    • Associated with warm-type antibodies (IgG)
    • Associated with cold-type antibodies (IgM)
    • Mixed phenomenon involving both types
  • Isoimmune Hemolytic Anemias:
    • Examples include hemolytic disease of the fetus and newborn (HDFN), caused by blood group incompatibilities

Warm-Type Autoimmune Hemolytic Anemia

Table 16.3: Comparison of Warm and Cold AIHA
  • Optimal Temperature of Reactivity: Warm reactions peak at 37°C; cold peptides react optimally at 4°C.
  • Immunoglobulin Class: Warm AIHA involves primarily IgG, whereas cold AIHA is predominantly IgM.
  • Hemolysis Site: Predominantly extravascular in warm AIHA and intravascular in cold AIHA.

Additional Hemolytic Anemias

Cold-Type Autoimmune Hemolytic Anemia
  • AIHA associated with cold-type autoantibody typically results in erythrocytes being coated with IgM.
  • Complex interplay exists between warm and cold autoantibodies, leading to varying mechanisms of hemolytic action.

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Etiology
  • PNH is an acquired, clonal disorder resulting from a nonmalignant expansion of stem cell lines.
  • Mutations in the PIGA gene disrupt presentation of protective G protein-coupled receptors, enhancing susceptibility to hemolysis.
Epidemiology
  • A percentage of PNH cases evolve from or into aplastic anemia.
  • Roughly 5% to 10% of patients may develop acute myelogenous leukemia.
  • Median diagnosis age is 42 years, with a survival outlook generally around 10 years post-diagnosis.
Clinical Features
  • Onset typically occurs between ages 30 and 60 years, characterized by episodes of hemoglobinuria, especially during sleep.
Laboratory Findings
  • Presentation may include severe anemia with hemoglobin levels < 6 g/dL.
  • Peripheral blood smears could reveal hypochromic and microcytic RBCs due to iron deficiency from lysis.
  • Diagnostically significant are findings from tests such as sucrose hemolysis test and Ham's test, along with flow cytometry to detect deficiencies in critical CD markers.