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)
  • Can be caused by:
  • Absolute Iron Deficiency:
    • Represents a decrease in total body iron caused by:
    • Blood loss
    • Decreased intake of iron
    • Increased utilization of iron
  • Functional Iron Deficiency:
    • Represents inadequate utilization of iron stores, illustrated by iron sequestration syndromes such as Anemia of Chronic Disease (ACD) and Anemia of Chronic Inflammation (ACI).

Causes of Iron Overload

• Iron overload can result from:
  • Inherited alterations affecting iron uptake and retention
  • Chronic disorders like sideroblastic anemia
  • Iron therapy or blood transfusion
  • Hemolytic anemias
  • Hereditary hemochromatosis (HH)

Early Diagnosis

• Essential for:
  • Nonanemic infants and toddlers under 2 years of age
  • Pregnant women to reduce maternal-fetal morbidity

Factors in Iron Deficiency Anemia

• Excessive Loss: Pathological or physiological blood loss
• Nutritional Deficiency: Inadequate intake of iron
• Increased Physiological Demand: e.g., during growth spurts, pregnancy
• Faulty or Incomplete Absorption: Absorption issues due to conditions such as celiac disease or small bowel resection

Etiology of Iron Deficiency Anemia

• Decreased iron intake: e.g., meat-poor diets
• Faulty absorption: e.g., small bowel resection, celiac disease
• Increased iron utilization: e.g., during growth spurts
• Pathological iron loss: e.g., gastrointestinal bleeding, malignancy
• Physiological iron loss: e.g., pregnancy, menstruation

Pathophysiology of Iron Deficiency

• Sequential Phases:
  • Stage 1 (Prelatent): Decrease in storage iron (ferritin)
  • Stage 2 (Latent): Decrease in functional and circulating iron leading to
  • 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 and Hematocrit - H&H)
  • Decrease in oxygen delivery to peripheral tissues

Laboratory Characteristics of IDA

• Hematology:

  • IDA progresses with results shifting as the disease advances:
  • Mean Corpuscular Volume (MCV): initially normocytic, eventually microcytic
  • Mean Corpuscular Hemoglobin Concentration (MCHC): starts normochromic but becomes hypochromic
  • Reticulocyte count: Typically normal or low due to ineffective erythropoiesis
  • Decreased RBC, H&H in latent stages; may be normal in early stages
  • Elevated platelet count and white blood cell count may be noted due to EPO/TPO homology

• Characteristics of Ineffective Erythropoiesis:

  • Iron deficiency causes concurrent negative effects on RBC production and hemoglobin production, reflected by reticulocyte production decreases.
  • Reticulocyte hemoglobin content (CHr) serves as an effective early indicator of iron deficiency, particularly crucial for infants and toddlers due to risks for cognitive difficulties.

Clinical Chemistry Studies

• Serum Iron: Measures circulating iron bound to transferrin
• Transferrin Saturation: Measures percentage of transferrin occupied by iron
• Serum Ferritin: Measures storage iron
• Soluble Transferrin Receptor (sTfR): Measures concentration of soluble transferrin receptor

Iron Studies: Comparison Table

Comparison: IDA versus ACD (Anemia of Chronic Disease)

Other Laboratory Characteristics

• Hypercellular marrow present with normal reticulocyte count.
• Mature nonnucleated RBCs typically hypochromic with normocytic and/or microcytic characteristics may be observed.
• Basophilic stippling or Pappenheimer bodies with demorphic cell populations may also be present.

Chapter 15: Macrocytic and Megaloblastic Anemias

Macrocytic Anemias

• Characterized by macrocytosis, which is an increased MCV (usually between 100 and 120 fL) observable in megaloblastic anemia but can result from non-megaloblastic etiologies.
• Nonmegaloblastic Macrocytic Anemias: Lack a common pathophysiology.

Megaloblastic Anemias

• Defined by:
  • Hypercellular marrow with nuclear-cytoplasmic asynchrony
  • Intramedullary cell death due to ineffective erythropoiesis
  • Presence of leukopenia and thrombocytopenia
• Two major causes:
  • Vitamin B12 (cobalamin, Cbl) deficiency
  • Folic acid deficiency

Etiology of Vitamin B12 Deficiency

• Increased utilization due to infections caused by parasitic entities like Diphyllobothrium latum (tapeworm)
• Pathogenic bacteria linked with disorders like diverticulitis or small-bowel stricture
• Malabsorption syndromes following gastric resection, carcinoma, or particular forms of celiac disease
• Inflammatory disorders of the terminal ileum
• Nutritional deficiency or reduced supply of B12

Pernicious Anemia (PA)

• Etiology:
  • May link to autoimmune endocrinopathies and antireceptor autoimmune diseases such as:
  • Chronic autoimmune thyroiditis (Hashimoto’s thyroiditis)
  • Insulin-dependent diabetes mellitus
  • Addison’s disease
  • Primary ovarian failure
  • Primary hypoparathyroidism
  • Graves’ disease
  • Myasthenia gravis

Epidemiology

• Research recently indicated that 1.9% of people over 60 years have undiagnosed pernicious anemia.
• Previous studies suggested the disease primarily affected Northern Europeans; however, more recent studies show its presence in Black and Latin American populations.
• Median age at diagnosis: 60 years; slightly more women than men affected.

Physiology of B12 and Folate

• Folate: Necessary for producing thymidine nucleotides for DNA synthesis.
• Vitamin B12: Source of folate is 5-methyltetrahydrofolate. The methyl group is removed to form tetrahydrofolate which detoxifies homocysteine into methionine.
• The removal of the methyl group is mediated by Vitamin B12.

Clinical Signs and Symptoms

• Possible skin color changes to a lemon-yellow appearance.
• Hyperpigmentation seen in nail beds, skin creases, and periorbital areas due to melanin deposition.
• Symptoms may include angular cheilitis, dyspepsia, diarrhea, glossitis, and painful tongue.
• Early graying of hair, tiredness, dyspnea on exertion, vertigo, tinnitus, and potential cardiovascular issues like congestive heart failure and palpitations or angina.
• Neurological and cognitive abnormalities may also occur.

Laboratory Findings for Megaloblastic Anemia

• Low hemoglobin, microhematocrit, and RBC count.
• Mean Corpuscular Volume (MCV) can reach 130 fL.
• Mean Corpuscular Hemoglobin (MCH) commonly increased in 90% of cases.
• Moderate to significant anisocytosis and poikilocytosis observed.
• Presence of macrocytic, ovalocytic red cell precursors, especially metarubricytes.

Megaloblastic Anemia Testing

Clinical Chemistry Findings

• Serum haptoglobin-binding capacity decreased.
• Serum vitamin B12 and folate levels decreased, normal for folate.
• Serum iron increased; Total Iron Binding Capacity (TIBC) normal or decreased.
• Percent transferrin increased.
• Elevated serum lactic dehydrogenase isoenzymes (1 & 2) noted, significant increasing diagnostics, often implying hemolysis.
• Unconjugated bilirubin elevated, and urinary methylmalonic acid and homocysteine levels will be high as well.
• Low uric acid levels due to DNA synthesis reduction.

Folic Acid Deficiency: Etiology

• Absorption interference through drugs or medications.
• Increased utilization associated with pregnancy or conditions like acute leukemia.
• Antimetabolitic treatment affecting folate usage and absorption.

Sources of Folates

• Found in yeast, green leafy vegetables, organ meats like liver and kidneys.
• The human body stores limited amounts, typically between a 3 to 4 months supply.
• Chronic inadequate diet leading to deficiency can yield megaloblastic anemia.
• Alcohol is a prominent pharmacological cause of folic acid deficiency.

Epidemiology of Folic Acid Deficiency

• Lack of dietary folic acid especially from green leafy vegetables.
• Increased dietary demands in pregnancy and infancy.
• Malabsorption disorders such as sprue or gluten sensitivity hinder absorption.
• Biologic competition for dietary folate caused by bacterial overgrowth in the gut.
• Commonly linked with alcohol use.

Chapter 16: Hemolytic Anemias

Hemolytic Anemia (HA)

• The common feature is premature erythrocyte destruction, mainly initiated by trapping cells in spleen/liver (extravascular) or blood vessels (intravascular).
• Intrinsic Hemolytic Anemia Causes:
  • Hemoglobinopathies
  • RBC membrane defects
  • RBC enzyme defects
• Extrinsic Hemolytic Anemia Causes:
  • Vascular defects
  • Antibody and/or complement-related mechanisms
  • Infectious agents such as bacteria or parasites
  • Toxins or mechanical devices

Organizing Hemolytic Anemia

• Organized by:
  • Inherited vs Acquired
  • Intravascular vs Extravascular
  • Immune vs Non-Immune
• Increased bone marrow activity may compensate for RBC loss but failure to adequately increase production leads to anemia.
• Most anemias may possess a hemolytic aspect, and in marrow failure scenarios, the produced RBCs tend to be defective.
• Hemolysis can vary from being asymptomatic to life-threatening.

Membrane Disruption in Hemolytic Anemia

• Classified into:
  • Inherited (Intrinsic)
  • Acquired (Extrinsic)
• Further categorized based on the destruction site:
  • Intravascular
  • Extravascular

Intravascular versus Extravascular Hemolysis

Hemolytic Anemias Due to Genetic Disorders

• Hereditary Spherocytosis: Characterized by round RBCs, fragile, leading to hemolysis.
• Hereditary Elliptocytosis: Defect in cytoskeletal proteins, leading to elliptical-shaped RBCs.
• Hereditary Stomatocytosis: RBCs have abnormal permeability, resulting in altered shape.
• Acanthocytosis: RBCs become spiky in appearance, associated with liver disease.

Erythrocytic Enzyme Defects

• Disorders in erythrocyte metabolism fall under congenital nonspherocytic hemolytic anemia (CNSHA), which includes:
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency
  • Pyruvate kinase (PK) deficiency
  • Methemoglobin reductase deficiency
• The clinical presentations vary widely in severity and degree.

Acquired Hemolytic Anemia

Associated Microorganisms

Immune Mechanisms (Antibodies)

• Classification of Immune Hemolytic Anemia:
  • Autoimmune Hemolytic Anemias:
  • Associated with warm-type antibodies
  • Associated with cold-type antibodies
  • Associated with both warm and cold-type antibodies
  • Isoimmune Hemolytic Anemias:
  • Hemolytic disease of the fetus and newborn (HDFN)
    • Rh incompatibility
    • ABO incompatibility
  • Drug-Induced Hemolytic Anemia:
  • Adsorption of immune complexes to the red cell membrane
  • Adsorption of drugs to red cell membrane
  • Induction of autoantibodies to drugs
  • Nonimmunological adsorption of immunoglobulin to red blood cell membrane

Warm-Type Autoimmune Hemolytic Anemia

Other Types of Hemolytic Anemia

• Cold-type Autoimmune Hemolytic Anemia: Typically associated with IgM cold agglutinin antibodies.
• AIHA with Warm and Cold Autoantibodies: Characterized by IgG warm antibodies, complement activation, and IgM cold agglutinins working simultaneously.

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Etiology

• A rare, acquired clonal disorder resulting from the nonmalignant expansion of stem cell lines.
• Pathophysiology: Mutations in the gene phosphatidylinositol glycan-A (PIGA) lead to the absence of important G protein-coupled receptors on hematopoietic cell surfaces, such as CD55 and CD59, which minimize complement binding.

Epidemiology

• 25% of PNH cases may evolve from aplastic anemia, while 5% to 10% may develop into acute myelogenous leukemia.
• Median diagnosis age: 42 years (range of 16 to 75).
• Median survival post-diagnosis typically noted at around 10 years with potential for spontaneous long-term remission.

Clinical Signs and Symptoms

• Insidious onset between ages 30 to 60
• Irregular episodes of hemoglobinuria occur, particularly during sleep, a notable manifestation of PNH

Laboratory Findings

• Severe anemia with hemoglobin levels often below 6 g/dL.
• Peripheral blood smears may reveal hypochromic, microcytic RBCs if an iron-deficiency state has developed due to hemolysis.
• Increased autohemolysis noted after 48 hours, with additional hemolysis heightened by glucose addition in testing.
• Specific diagnostic tests include:
  • Sucrose hemolysis (sugar-water) test
  • Ham’s test (acid-serum lysis)
  • Detection of absent CD markers through flow cytometry is increasingly common in diagnosing PNH.