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Landon Center on Aging

Landon Center on Aging  :  Geriatric Education & Training

Hypoproliferative Anemia

Instructor: Mary McDonald, MD

 

Specific Learning Objectives:

A. Learning Objectives - Medical Students should be able to:

  1. List common clinical signs and symptoms of anemia
  2. Define hypoproliferative anemia
  3. Define 3 RBC indices and describe how differences in these indices can help identify type of anemia
  4. Outline the laboratory workup of anemia including CBC with differential, reticulocyte count, iron studies and bilirubin
  5. Describe the basis of classification of microcytic, normocytic and macrocytic anemia
  6. Summarize the absorption of iron from dietary sources and include daily requirements for men and women
  7. Discuss risk factors associated with iron deficiency
  8. Describe the clinical features observed in iron deficiency anemia
  9. Compare and contrast the unique histopathologic findings that help differentiate the different types of hypoproliferative anemias.
  10. Summarize the pathophysiology of anemia of chronic disease
  11. Describe risk factors for folate or B12 deficiency from dietary sources
  12. Compare and contrast the clinical features of folate and B12 deficiency

B. Key Terms

Mean Corpuscular Volume Iron Deficiency Anemia
Red Cell Distribution Width

Anemia of Chronic Disease

Mean Corpuscular Hemoglobin

Megaloblastic Anemia

Reticulocyte Count

Glossitis

Bilirubin

Angular Stomatitis

Serum Iron

Koilonychia
Total Iron-Binding Capacity

Plummer-Vinson Syndrome
Ferritin Folate
Macrocytosis Vitamin B12
Microcytosis Intrinsic Factor
Hypoproliferative Anemia Pernicious Anemia

C. Module Content:

  1. Clinical Signs and Symptoms of Anemia
  2. Laboratory Workup the Patient with Anemia
  3. Hypoproliferative Anemias
  4. Microcytic Anemias
  5. Macrocytic Anemias

D. Readings:

Suggested References:

Current Medical Diagnosis & Treatment 2007. Hematology. Charles A. Linker, MD
http://www.accessmedicine.com.proxy.kumc.edu:2048/content.aspx?aID=5523&searchStr=thalassemia

Harrison’s Internal Medicine. Chapter 90. Iron Deficiency and Other Hypoproliferative Anemias. http://www.accessmedicine.com.proxy.kumc.edu:2048/content.aspx?aID=64038&searchStr=hypoproliferative+anemia

Taber Medical Dictionary 20th Edition

 

I. CLINICAL SIGNS AND SYMPTOMS OF ANEMIA

  • Pallor
  • Rapidly bounding pulse
  • Faintness
  • Dyspnea on exertion
  • Easy fatigueability
  • Dependent edema - if heart failure or concomitant hypoalbuminemia
  • Systolic flow murmurs

II. LABORATORY WORKUP OF THE PATIENT WITH ANEMIA

  • CBC with differential
    • Includes hemoglobin and hematocrit levels but also the RBC indices which are very helpful in identification of the type of anemia
      • Mean Corpuscular Volume (MCV)- The average volume RBCs.
        • Increased/Macrocytosis-Megaloblastic anemia, reticulocytosis, hypothyroidism
        • Decreased/Microcytosis-iron deficiency, thalassemia, lead poisoning
        • Normal-Anemia of chronic disease, acute blood loss
      • Red Cell Distribution Width (RDW)- A measure of anisocytosis(variation on RBC size)
        • Increased in many types of anemia (iron deficiency, pernicious, folate deficiency, thalassemia
  • Reticulocyte Count
    • Young RBCs that still contain small amounts of RNA Click here
    • A simple measure of production of erythrocytes
    • 1/120th of total RBCs normally
    • The normal response to blood loss or increased destruction of RBCs would be an increase in reticulocyte count
    • Normal or low reticulocyte count in an anemic patient may indicate a hypoproliferative disorder.
  • Bilirubin
    • 80% of normal Bilirubin production is a result of the degradation of hemoglobin Click here
    • In the absence of liver disease Indirect Bilirubin is an excellent indicator of RBC destruction
    • LDH and Haptoglobin are other markers

    Low Retic Count and Normal Bili/LDH

    Hypoproliferative Anemias

    High Retic Count and High Bili/LDH

    Hemolytic Anemia

    Low Retic Count and High  Bili/LDH

    Ineffective Erythropoiesis

    High Retic Count and Normal Bili/LDH

    Blood Loss
  • Iron Studies
    • Serum iron
    • TIBC-Total Iron-Binding Capacity. Represents the amount of circulating iron bound to transferrin
    • Ferritin-correlates with total-body iron stores. Iron bound to protein as ferritin within cells.

    Iron

    TIBC

    Ferritin

    Fe Deficiency

    Low

    High

    low

    Anemia of Chronic Disease

    Low

    Low

    Normal to high

     

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III. HYPOPROLIFERATIVE ANEMIAS

  • Represent absolute or relative bone marrow failure. The erythroid marrow has not proliferated appropriately in response to anemia
  • In response to acute anemia (i.e. blood loss) the healthy marrow is capable of producing erythrocytes 6-8 times the normal rate (mediated through erythropoietin)
    • Microcytic (MCV < 80fL)
      • iron deficiency anemia
      • thalassemia these (this topic not covered in this module)
      • congenital, x-linked recessive type sideroblastic anemia (this topic not covered in this module)
      • anemia of chronic disease
    • Macrocytic (MCV > 100fL)
      • Megaloblastic anemia
      • Acquired sideroblastic anemias (this topic not covered in this module)

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IV. MICROCYTIC ANEMIAS

  1. Iron Deficiency Anemia

Iron absorption is a highly regulated process and occurs primarily in the proximal small intestine Click here.  There is no excretory process for iron and iron is lost only through blood loss or that lost from exfoliation of epidermal cells.  The amount of iron required daily to replace that lost is 1.0 mg of elemental iron in men and 1.4 mg of elemental iron in women of childbearing age. 

Once absorbed, iron is highly conserved by the body.  The iron attached to heme in RBCs is recycled when the RBC reaches the end of its’ lifespan and is degraded by phagocytosis.  The iron component of heme is released to the carrier protein, transferrin, and is delivered to the bone marrow to be used once again in young RBCs.  The hemoglobin is converted to bilirubin. Click here

Iron in free form is highly toxic to cells and is therefore found within cells attached to a carrier protein as ferritin.  Serum ferritin level is a convenient laboratory value that corresponds well to iron stores.  The average ferritin level in men is 100 mcg/L and in women is 30 mcg/L and these levels fall with decreases in iron stores.

  • Who is at risk for Iron Deficiency? 3 groups at risk.
    1. Increased Need for Iron
      • During periods of rapid growth (early childhood and adolescence)
      • Pregnancy
      • Lactation
    2. Poor intake or Absorption of Iron
      • Achlorhydria
      • Inflammatory bowel disease
      • Cow’s milk instead of formula in newborns
      • Commonly found following gastric bypass surgery
    3. Increased Loss of Iron
      • Menstruation
      • GI bleeding
      • Tissue loss (i.e., burns or psoriasis)
      • Urinary loss
      • Iatrogenic

  • Clinical Features of Iron Deficiency Anemia
  • What do Iron Deficient RBCs look like? Click here
    • Hypochromic, microcytic
    • Decreased stainable iron on smear
    • Small, ragged RBC precursors

  • What do the labs look like in Iron Deficiency?
    • Low serum iron levels
    • High TIBC
    • Low ferritin
    • Normal or low MCV (depending on severity of iron deficiency)
  1. Anemia of Chronic Disease
    • Definition: Anemia commonly associated with certain disease states due to excessive cytokine release. (aka, infections, inflammation , and cancer, autoimmune disease)
    • Pathophysiology
      • Decreased RBC lifespan
      • Direct inhibition of RBC progenitors
      • Relative reduction in EPO levels
      • Decreased availability of Iron. Cytokines prevent iron release from macrophages to be recycled during hematopoeisis.
    • Histopathology
      • Normocytic or microcytic anemia
      • No anisocytosis
      • Anisopoikilocytosis
 

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V. MACROCYTIC ANEMIAS

By far the most common causes are liver disease, alcohol intake and myelodysplastic syndromes.  Megaloblastic anemia is only one cause of macrocytic anemia. Other causes are hypothyroidism and brisk hemolysis.

  1. Megaloblastic Anemia
  • Caused by impaired DNA synthesis
  • Most commonly caused by folate or vitamin B12 (cobalamin) deficiency click here
  • Presence of megaloblastic cells on histologic exam is the hallmark
    • larger than normal erythroid precursors with more cytoplasm relative to the size of the nucleus.
    • Condensation of chromatin to a homogenous mass effected
    • Oval macrocytes in combination with hypersegmented neutrophils (>five nuclear segments in at least 5 % of neutrophils
    1. Folic acid deficiency
      • Causes
        • Inadequate intake- Folate reserves are small and deficiency develops rapidly if not replaced through diet.  Typically found in the elderly, poor or alcoholic.  Can also be problematic in patients receiving hemodialysis as the folate is filtered out of the blood in the dialysis fluid.  Children raised on goats’ milk are at risk due to low folate levels in goats’ milk.  Alcohol may acutely depress serum folate levels, evan if folate stores are adequate.
        • Poor absorption-  Many illnesses or disease states are associated with poor absorption of folate from the small intestine
          • Dietary folates are absorbed in the duodenum and jejunum by a several -stage process.Click here
            1. pteroylheptaglutamate (PteGlu7) is first hydrolyzed at the enterocyte surface by intestinal brush-border folate hydrolase to pteroylglutamate (PteGlu or folic acid)
            2. Folic acid is transported by the reduced folate carrier into the enterocyte
            3. Here it undergoes further methylation and reduction to CH3H4PteGlu.
            4. The same reduced folate carrier protein transports both oxidized and reduced forms across the basolateral membrane
          • Many illnesses or disease states are associated:
            • Nontropical Sprue
            • Tropical Sprue
            • Regional enteritis
            • Diabetes mellitus
            • Whipple disease
            • Scleroderma
            • Amyloidosis
            • Lymphomatous or leukemic infiltration of the small intestine
            • Systemic bacterial infections
        • Increased requirement
          • Pregnancy- 5-10 fold increase in nutritional requirement of folate during pregnancy because folate is being transferred to the fetus.
          • Increased cell turnover- hemolytic anemia, exfoliative dermatitis
          • Methotrexate use
      • Clinical Signs/Complications of Folate Deficiency
        • Weight loss
        • Glossitis - an inflammation of the tongue
        • cheilitis
        • Megaloblastic anemia
        • Fetal neural tube defects
        • Elevated serum homocysteine levels and associated atherosclerosis
        • Deficiency perhaps associated with increased colon cancer risk
    2. Vitamin B12 Deficiency
      • Sources and Absorption
        • Vitamin B12 only found in foods of animal origin with no plant source
        • Deficiency more often due to failure to absorb Vitamin B12 rather than poor intake
        • Bound to intrinsic factor, a small glycoprotein secreted by the parietal cells of the gastric mucosa
        • Vitamin B12 deficiency impairs the metabolism of folic acid, leading to functional folate deficiency
        • VitaminB12 with intrinsic factor and is absorbed in the terminal ileum. Click here
        • It is stored by the body and typically a 7-12 year supply exists.
      • Pathogenesis
        • Pernicious anemia (intrinsic factor auto antibodies)
        • Gastrectomy
        • Ileum disease/resection
        • Fish tapeworm (Diphylobothrium latum)
      • Clinical features
        • Anemia
        • Neurologic deficits (dorsal columns)
          • Spastic paraparesis - Paraplegia characterized by increased muscular tone and accentuated tendon reflexes: seen in upper motor neuron diseases
          • Sensory ataxia- Ataxia resulting from interference in conduction of sensory responses, esp. proprioceptive impulses from muscles. The condition becomes aggravated when the eyes are closed. (think Romberg’s sign)
          • Dementia
        • Patients may not be anemic but may have neurologic sequelae and this may be exacerbated by folic acid replacement without B12 replacement.
        • In the elderly a B12 level on the low end of normal may signify occult B12 deficiency and high levels of methylmalonic acid (MMA) and homocysteine levels may be monitored to detect occult deficiency.

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