Hematology chapter 14

• Absolute iron deficiency and functional iron deficiency are both conditions characterized by insufficient iron for normal physiological functions, but they differ in their underlying causes and mechanisms.

Absolute Iron Deficiency

• Absolute iron deficiency is characterized by a true deficit in total body iron stores.
• It occurs when iron intake, absorption, or storage is inadequate to meet the body's needs or when iron losses exceed iron replenishment.
• Common causes include inadequate dietary iron intake, impaired iron absorption, and chronic blood loss.
• Conditions leading to iron deficiency anemia (IDA) include:
  • Inadequate dietary iron intake.
  • Impaired iron absorption (e.g., celiac disease).
  • Chronic blood loss (e.g., heavy menstruation, gastrointestinal bleeding).
  • Pregnancy (increased iron demand).
  • Rapid growth spurts in infants and adolescents.
• Inadequate dietary intake is prevalent in populations with limited access to iron-rich foods like meat, poultry, and fortified cereals; vegetarians and vegans are also at higher risk if they do not carefully manage their dietary iron sources.
• Impaired iron absorption can result from gastrointestinal disorders such as celiac disease, Crohn's disease, or surgical removal of parts of the stomach or small intestine, which reduces the surface area available for iron absorption.
• Chronic blood loss is a significant cause, stemming from conditions such as heavy menstrual bleeding (menorrhagia), gastrointestinal bleeding (from ulcers, polyps, or colorectal cancer), and frequent blood donation.
• The body's iron stores, including ferritin and hemosiderin, are depleted.
• Serum ferritin levels, which reflect iron storage, are typically low (less than 15 ng/mL).
• Transferrin saturation, which indicates the proportion of transferrin bound to iron, is also reduced (less than 20%).
• Red blood cell production is impaired due to the lack of available iron for heme synthesis, leading to microcytic (small) and hypochromic (pale) red blood cells.
• Hemoglobin levels decrease, resulting in anemia.
• Symptoms include fatigue, weakness, pale skin, shortness of breath, headache, dizziness, and brittle nails.
• Iron supplementation, either orally or intravenously, is the primary treatment. The route depends on the severity of the deficiency and the individual's ability to absorb oral iron.
• Addressing the underlying cause of the iron loss or malabsorption is crucial for long-term management.
• Vulnerable groups include:
  • Infants and young children due to rapid growth and increased iron requirements.
  • Women of childbearing age, especially those with heavy menstrual bleeding or who are pregnant.
  • Individuals with chronic diseases affecting iron absorption or causing chronic blood loss.
• Iron Deficiency Anemia (IDA) is a common type of anemia caused by insufficient iron
• Iron is essential for hemoglobin synthesis, which carries oxygen in red blood cells
• Laboratory findings in IDA include:
  • Decreased serum ferritin levels.
  • Decreased hemosiderin stores in the bone marrow.
  • Increased levels of transferrin.
  • Elevated total iron binding capacity (TIBC).
• IDA progresses through several stages, each characterized by specific changes in red blood cell (RBC) morphology

Stages of Iron Deficiency

• Iron deficiency develops in stages, starting with depletion of iron stores and progressing to anemia

Stage 1: Iron Store Depletion

• This is the earliest stage of iron deficiency
• Iron stores in the bone marrow, liver, and spleen are reduced
• Serum ferritin levels decrease, indicating reduced iron storage
• RBC morphology is usually normal in this stage
• Red blood cell indices such as hemoglobin (Hb), mean corpuscular volume (MCV), and red cell distribution width (RDW) are typically within the normal range

Stage 2: Iron-Deficient Erythropoiesis

• Iron stores are fully depleted
• Iron supply to the bone marrow becomes insufficient to support normal RBC production
• Serum iron levels decrease, and transferrin saturation (the percentage of transferrin bound to iron) decreases
• Erythrocyte protoporphyrin levels increase because protoporphyrin cannot be incorporated into heme due to iron deficiency
• RBC morphology may still appear normal
• However, subtle changes can begin to appear:
  • Anisocytosis (variation in RBC size) may be present
  • Poikilocytosis (variation in RBC shape) may be seen
  • Reticulocyte hemoglobin content (CHr) starts to decrease

Stage 3: Iron Deficiency Anemia

• This is the final stage, characterized by a significant decrease in hemoglobin levels and noticeable changes in RBC morphology
• Anemia is present, with hemoglobin levels below the normal range
• Red blood cells are microcytic (smaller than normal) and hypochromic (paler than normal)
• MCV is typically below 80 fL
• Mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) are also reduced
• Red cell distribution width (RDW) is increased, indicating a greater variation in red blood cell size

RBC Morphology in IDA

• The morphological features of red blood cells in iron deficiency anemia are key to diagnosis
• Common findings include:
  • Microcytosis:
    • Red blood cells are smaller than normal
    • The central pallor (the light area in the center of the RBC) is increased
  • Hypochromia:
    • Red blood cells appear paler than normal due to reduced hemoglobin content
    • The zone of central pallor occupies more than one-third of the cell diameter
  • Anisocytosis:
    • Variation in red blood cell size
    • Both microcytes and normal-sized cells may be present
    • RDW is elevated
  • Poikilocytosis:
    • Variation in red blood cell shape
    • Several abnormal shapes may be observed
  • Target Cells:
    • These cells have a central, dark spot (hemoglobin) surrounded by a ring of pallor, and then an outer ring of hemoglobin
    • They result from an increased surface area-to-volume ratio
  • Elliptocytes:
    • Oval or elongated red blood cells
    • Less commonly seen but can occur in severe cases
  • Pencil Cells:
    • Thin, elongated cells resembling a pencil
    • Characteristic of iron deficiency anemia
  • Schistocytes (Helmet Cells):
    • Fragmented red blood cells, usually indicative of microangiopathic hemolytic anemia
    • Rarely seen in uncomplicated IDA, but may occur if there are other underlying conditions
  • Teardrop Cells (Dacrocytes):
    • Red blood cells shaped like teardrops
    • Not specific to IDA but may be present
  • Thrombocytosis:
    • Elevated platelet count
    • Frequently observed in iron deficiency anemia

Summary of RBC Morphology by Stage

• Stage 1 (Iron Store Depletion):
  • Normal RBC morphology
• Stage 2 (Iron-Deficient Erythropoiesis):
  • Possible mild anisocytosis and poikilocytosis
  • Decreased CHr
• Stage 3 (Iron Deficiency Anemia):
  • Microcytosis and hypochromia
  • Anisocytosis (increased RDW)
  • Poikilocytosis (target cells, elliptocytes, pencil cells, teardrop cells)

Functional Iron Deficiency

• Functional iron deficiency occurs when total body iron stores are adequate, but iron is not readily available for erythropoiesis (red blood cell production).
• It is often associated with chronic inflammation, infection, or malignancy.
• Conditions such as chronic kidney disease (CKD), heart failure, autoimmune disorders (rheumatoid arthritis, lupus), and cancer can trigger a state of functional iron deficiency.
• Inflammatory cytokines, such as interleukin-6 (IL-6), hepcidin, are elevated.
• Hepcidin is a hormone produced by the liver that regulates iron homeostasis.
• Elevated hepcidin levels inhibit iron release from macrophages and reduce iron absorption in the small intestine by binding to ferroportin, the iron export channel.
• Iron is trapped within macrophages and liver cells, preventing its transport to the bone marrow for red blood cell production.
• Serum ferritin levels are normal or elevated due to the inflammatory response, making it difficult to assess true iron status.
• Transferrin saturation is typically low or normal.
• Although iron stores are present, the availability of iron for erythropoiesis is limited, leading to normocytic (normal size) or microcytic anemia.
• Hemoglobin levels decrease, resulting in anemia.
• Symptoms are similar to those of absolute iron deficiency: fatigue, weakness, pale skin, shortness of breath, headache, and dizziness.
• Management involves addressing the underlying inflammatory condition.
• Iron supplementation alone may not be effective because the iron cannot be properly utilized due to hepcidin-mediated block.
• Erythropoiesis-stimulating agents (ESAs) are often used to stimulate red blood cell production, particularly in patients with chronic kidney disease. However, ESAs may require concurrent iron supplementation to be effective.
• Intravenous iron is frequently used to bypass the hepcidin-mediated absorption block and deliver iron directly to the bone marrow.
• Monitoring iron status and adjusting treatment based on the patient's response and underlying condition is essential.

Comparison

• Cause: Absolute iron deficiency results from inadequate total body iron stores, while functional iron deficiency occurs despite adequate stores due to impaired iron mobilization.
• Iron Stores: In absolute iron deficiency, iron stores (ferritin) are low, whereas in functional iron deficiency, they are normal or high.
• Hepcidin: Hepcidin levels are typically normal or low in absolute iron deficiency but are elevated in functional iron deficiency due to inflammation.
• Red Blood Cell Characteristics: Both conditions can lead to anemia, but absolute iron deficiency typically results in microcytic, hypochromic red blood cells, while functional iron deficiency can result in normocytic or microcytic red blood cells.
• Response to Iron Supplementation: Absolute iron deficiency responds well to iron supplementation, while functional iron deficiency may not respond effectively unless the underlying inflammation is controlled or intravenous iron is administered.

Contrast

• Absolute iron deficiency is typically caused by dietary insufficiency, impaired absorption, or blood loss.
• Functional iron deficiency is primarily associated with chronic inflammatory conditions that disrupt iron homeostasis.
• Laboratory findings in absolute iron deficiency include low serum ferritin and transferrin saturation.
• Functional iron deficiency presents with normal or elevated serum ferritin but low transferrin saturation.
• Treatment for absolute iron deficiency focuses on replenishing iron stores through oral or intravenous supplementation.
• Functional iron deficiency requires addressing the underlying inflammatory condition and may involve intravenous iron, ESAs, or other therapies.

Primary vs Secondary Overload Disorders

• Primary overload disorders are caused by inherent defects in metabolic pathways.
• Secondary overload disorders arise as complications of other diseases or conditions.

Primary Overload Disorders

• Typically result from genetic mutations affecting specific enzymes or transport proteins involved in metabolic processes.
• These mutations lead to the accumulation of specific substances within cells or tissues, causing a variety of clinical manifestations.
• The accumulation occurs because the defective enzyme or transport protein cannot efficiently process or remove the substance.
• Examples encompass a wide spectrum of inherited metabolic disorders, each characterized by the buildup of a particular compound.
• Hemochromatosis (Hereditary Hemochromatosis) is a primary iron overload disorder caused by mutations affecting iron metabolism, leading to excessive iron absorption and accumulation in organs such as the liver, heart, and pancreas.
• Wilson's disease is a primary copper overload disorder resulting from mutations in a gene encoding a copper-transporting ATPase, leading to impaired copper excretion and accumulation, mainly in the liver and brain.
• Glycogen storage diseases are a group of primary overload disorders characterized by defects in enzymes involved in glycogen synthesis or breakdown, leading to abnormal glycogen accumulation in the liver, muscles, and other tissues.
• Lysosomal storage disorders: These disorders encompass a range of genetic conditions characterized by deficiencies in lysosomal enzymes, resulting in the accumulation of undegraded substrates within lysosomes.

Secondary Overload Disorders

• Develop as a consequence of other underlying diseases, environmental factors, or acquired conditions.
• In these disorders, the metabolic pathways themselves are typically intact, but external factors disrupt the normal balance of substance metabolism, leading to overload.
• Secondary iron overload can arise from conditions such as multiple blood transfusions, chronic liver disease, or iron supplementation.
• Transfusions can lead to the accumulation of iron in the body, as each unit of transfused blood contains a significant amount of iron.
• Liver disease can impair the liver's ability to regulate iron metabolism.
• Long-term iron supplementation, particularly in individuals with underlying risk factors, can contribute to iron overload.
• Secondary copper overload can occur in conditions such as cholestatic liver disease, where impaired bile flow leads to the retention of copper in the liver.
• Certain medications or toxins can also interfere with copper metabolism, resulting in copper accumulation.
• Acquired lysosomal storage disorders are rare but can occur due to exposure to certain drugs or toxins that inhibit lysosomal enzyme function.
• These acquired disorders mimic the clinical features of inherited lysosomal storage disorders but are not caused by genetic mutations.

Distinguishing Primary and Secondary Overload Disorders

• The underlying cause differentiates primary and secondary overload disorders.
• Primary disorders stem from inherent genetic defects affecting metabolic pathways.
• Secondary disorders arise as complications of other diseases or conditions.
• Genetic testing plays a crucial role in diagnosing primary overload disorders by identifying specific mutations in relevant genes.
• In secondary disorders, genetic testing is typically not informative, as the underlying metabolic pathways are usually intact.
• Family history can provide clues to the presence of primary overload disorders, as these conditions often exhibit familial inheritance patterns.
• Secondary disorders may not show a clear familial pattern unless the underlying predisposing condition is inherited.
• Biochemical testing helps assess the levels of specific substances that accumulate in overload disorders.
• In primary disorders, biochemical testing reveals characteristic patterns of metabolite abnormalities.
• In secondary disorders, the patterns of metabolite accumulation may be less specific and can vary depending on the underlying cause.
• Treatment strategies differ between primary and secondary overload disorders.
• Primary disorders often require targeted therapies aimed at correcting the underlying metabolic defect or reducing the accumulation of the offending substance.
• Therapeutic approaches may include enzyme replacement therapy, substrate reduction therapy, chelation therapy, or hematopoietic stem cell transplantation.
• Secondary disorders are typically managed by addressing the underlying cause and implementing supportive measures to alleviate symptoms and prevent complications.
• Treatment may involve managing the underlying disease, discontinuing offending medications, or implementing dietary modifications.

Examples

• Primary hemochromatosis (HFE-related) vs. secondary iron overload due to multiple blood transfusions.
• Wilson's disease (ATP7B mutations) vs. secondary copper overload due to cholestatic liver disease.
• Gaucher disease (GBA mutations) vs. acquired lysosomal storage disorder due to drug-induced enzyme inhibition.

Key Considerations

• The distinction between primary and secondary overload disorders is crucial for accurate diagnosis, appropriate management, and genetic counseling.
• A thorough evaluation, including genetic testing, biochemical analysis, and family history assessment, is essential to determine the underlying cause of an overload disorder.
• A Multidisciplinary approach involving specialists in genetics, metabolism, hepatology, and other relevant fields is often necessary to effectively manage these complex disorders.

Iron Metabolism Physiology

• Iron metabolism is tightly regulated to ensure adequate iron supply for essential processes while preventing iron overload.
• Dietary iron exists in two forms: heme iron (from animal sources) and non-heme iron (from plant sources and fortified foods).
• Heme iron is absorbed more efficiently than non-heme iron.
• Non-heme iron must be converted to its ferrous (Fe2+) form by duodenal cytochrome B reductase (Dcytb) on the enterocyte's apical surface for absorption.
• The absorption of Fe2+ across the apical membrane of enterocytes is mediated by the divalent metal transporter 1 (DMT1).
• Once inside the enterocyte, iron can be stored as ferritin or transported across the basolateral membrane by ferroportin.
• Ferroportin is the only known iron export channel in mammals.
• Iron export requires oxidation of Fe2+ to Fe3+ by hephaestin (a copper-dependent ferroxidase) or ceruloplasmin.
• In plasma, Fe3+ binds to transferrin, which transports iron to various tissues, including the bone marrow for erythropoiesis.
• Transferrin delivers iron to cells via transferrin receptor 1 (TfR1) on the cell surface.
• The transferrin-TfR1 complex is internalized via endocytosis, iron is released in the endosome, and TfR1 is recycled back to the cell surface.
• Hepcidin, produced by the liver, is the central regulator of iron homeostasis.
• Hepcidin binds to ferroportin, causing its internalization and degradation, thereby inhibiting iron export from enterocytes, macrophages, and hepatocytes.
• Iron is stored primarily in hepatocytes and macrophages as ferritin.
• Ferritin is a spherical protein shell that can store up to 4,500 iron atoms.
• Iron is recycled from senescent red blood cells by macrophages in the spleen and liver.
• This recycled iron accounts for the majority of iron used in erythropoiesis.
• Iron losses occur through menstruation, bleeding, and shedding of skin and gastrointestinal cells. There is no regulated mechanism for iron excretion.

Signs and Symptoms of Iron Deficiency Anemia (IDA)

• Fatigue and Weakness: A primary symptom due to reduced oxygen delivery to tissues.
• Pale Skin: Caused by lower hemoglobin levels reducing the red color of the blood.
• Shortness of Breath: The body attempts to compensate for reduced oxygen-carrying capacity.
• Headache: Decreased oxygen supply to the brain can trigger headaches.
• Dizziness or Lightheadedness: Related to reduced oxygen delivery to the brain.
• Brittle Nails (Koilonychia): Nails may become thin, brittle, and spoon-shaped.
• Hair Loss: Iron deficiency can disrupt the hair growth cycle.
• Pica: Unusual cravings for non-nutritive substances like ice, dirt, or clay.
• Restless Legs Syndrome (RLS): An urge to move the legs, often accompanied by uncomfortable sensations.
• Glossitis: Inflammation or soreness of the tongue.
• Angular Cheilitis: Cracking and inflammation at the corners of the mouth.
• Cold Hands and Feet: Due to poor circulation caused by anemia.
• Difficulty Concentrating: Reduced oxygen supply affects cognitive function.
• Increased Susceptibility to Infections: Iron is essential for immune function.
• Tachycardia (Rapid Heart Rate): The heart compensates for reduced oxygen-carrying capacity.
• Systolic Heart Murmur: A heart murmur may be audible due to increased cardiac output.
• Exercise Intolerance: Reduced oxygen delivery limits physical endurance.

Anemia of Inflammation (Anemia of Chronic Disease)

• Etiology:
  • Chronic infections (e.g., tuberculosis, HIV).
  • Autoimmune disorders (e.g., rheumatoid arthritis, lupus).
  • Chronic kidney disease (CKD).
  • Malignancy.
• Pathophysiology:
  • Inflammatory cytokines (IL-6) stimulate hepcidin production by the liver.
  • Elevated hepcidin reduces iron release from macrophages and decreases iron absorption in the gut by binding to and degrading ferroportin.
  • Iron is trapped within macrophages, limiting its availability for erythropoiesis.
  • Reduced erythropoietin (EPO) production or decreased responsiveness to EPO may also contribute.
• Laboratory Findings:
  • Hemoglobin: Low (anemia).
  • MCV: Usually normocytic (normal size), but can be microcytic in some cases.
  • Serum iron: Low.
  • TIBC: Low or normal.
  • Transferrin saturation: Low or normal.
  • Serum ferritin: Normal or increased (acute phase reactant).
  • Erythropoietin: inappropriately normal to low.

Sideroblastic Anemia

• Etiology:
  • Hereditary: Genetic mutations affecting enzymes involved in heme synthesis (e.g., ALAS2).
  • Acquired:
    • Myelodysplastic syndromes (MDS).
    • Alcohol abuse.
    • Lead poisoning.
    • Certain drugs (e.g., isoniazid).
• Pathophysiology:
  • Defective heme synthesis leads to iron accumulation in the mitochondria of erythroblasts.
  • Ringed sideroblasts (erythroblasts with iron-laden mitochondria surrounding the nucleus) are seen in the bone marrow.
  • Impaired hemoglobin production results in anemia.
• Laboratory Findings:
  • Hemoglobin: Low (anemia).
  • MCV: Can be microcytic, normocytic, or macrocytic.
  • Serum iron: High.
  • TIBC: Low or normal.
  • Transferrin saturation: High.
  • Serum ferritin: High.
  • Bone marrow: Ringed sideroblasts.
  • Elevated levels of erythrocyte protoporphyrin

Hereditary Hemochromatosis

• Etiology:
  • Genetic mutations affecting iron metabolism, most commonly in the HFE gene.
  • Other genes involved include HAMP, HJV, TFR2, and FPN1.
• Pathophysiology:
  • Increased intestinal iron absorption due to decreased hepcidin production (in HFE-related hemochromatosis).
  • Iron accumulates in various organs, including the liver, heart, pancreas, and joints.
  • Iron overload leads to tissue damage and organ dysfunction.
• Laboratory Findings:
  • Serum iron: High.
  • TIBC: Low or normal.
  • Transferrin saturation: High (greater than 45%).
  • Serum ferritin: High (often >1000 ng/mL).
  • Liver function tests: Elevated (AST, ALT).
  • Genetic testing: Positive for HFE or other relevant gene mutations.
  • Liver biopsy: Iron deposition.

Porphyria

• Etiology:
  • Genetic mutations affecting enzymes in the heme synthesis pathway.
  • Different types of porphyria are associated with specific enzyme deficiencies.
• Pathophysiology:
  • Accumulation of specific porphyrin precursors in different tissues, leading to various clinical manifestations.
  • Acute porphyrias (e.g., acute intermittent porphyria) primarily affect the nervous system.
  • Cutaneous porphyrias (e.g., porphyria cutanea tarda) primarily affect the skin.
• Laboratory Findings:
  • Varies depending on the type of porphyria.
  • Urine porphyrins: Elevated.
  • Fecal porphyrins: Elevated.
  • Red blood cell porphyrins: Elevated.
  • Genetic testing: Can identify specific gene mutations.
  • Specific enzyme assays to confirm the type of porphyria.

Disorders of Globin Synthesis (Thalassemia)

• Etiology:
  • Genetic mutations affecting the synthesis of globin chains (alpha or beta) in hemoglobin.
  • Alpha-thalassemia: Mutations or deletions in the alpha-globin genes.
  • Beta-thalassemia: Mutations in the beta-globin gene.
• Pathophysiology:
  • Reduced or absent synthesis of one or more globin chains.
  • Imbalance in globin chain production leads to ineffective erythropoiesis and hemolysis.
  • Excess of the unaffected globin chain precipitates, causing red blood cell damage.
• Laboratory Findings:
  • Hemoglobin: Low (anemia).
  • MCV: Usually microcytic and hypochromic.
  • Red blood cell count: Normal or elevated.
  • Peripheral blood smear: Target cells, fragmented cells, and nucleated red blood cells.
  • Hemoglobin electrophoresis: Abnormal hemoglobin fractions (e.g., increased HbF in beta-thalassemia).
  • Genetic testing: Can identify specific globin gene mutations or deletions.