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Megaloblastic Anemias

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Title: Megaloblastic Anemias


1
Chapter 7
  • Megaloblastic Anemias

2
1. Study Questions2. Homework Assignment3.
Exam for Unit III
3
Morphology of Human Blood and Marrow Cells
  • In Chapter 7, you will learn about megaloblastic
    anemias.  You will study Vitamin B12 deficiency
    and Folic Acid deficiency anemias.  The Schilling
    test for pernicious anemia is discussed. 
    Treatments for each type of anemia are covered. 
    Other non-megaloblastic, but macrocytic, anemias
    are discussed.

4
Megaloblastic Anemias
  • Group of disorders characterized by defective
    nuclear maturation caused by impaired DNA
    synthesis.
  • Manifested by presence of large and abnormal red
    cell precursors (megaloblastic) in bone marrow
    and macro-ovalocytes in peripheral blood, also
    see giant granulocyte precursor.

5
Biochemical Aspect
  • Defective nuclear maturation and megaloblastic
    morphology caused by decrease in thymidine
    triphosphate (TTP) synthesis from uridine
    monophosphate (UMP). Defect interferes with
    nuclear maturation, DNA replication, and cell
    division.
  • Primary causes for lack of thymidine and,
    consequently, defective DNA synthesis, are
    Vitamin B12 and folic acid deficiencies. Some
    drugs interfere with metabolism of these vitamins.

6
Clinical Manifestations of Megaloblastic Anemias
  • Degree of anemia ranges from mild to severe with
    symptoms of weakness, fatigue, shortness of
    breath and light-headedness. Congestive heart
    failure may/may not be present.
  • In severe anemia, may have lemon yellow skin tint
    because of mild jaundice and pallor. May see an
    increase in bilirubin. 

7
Ineffective Hematopoiesis 1 of 2
  • Megaloblastic anemia associated with ineffective
    erythropoiesis and hemolysis.
  • MCV gt 100 fL and as high as 160 fL. MCV reflects
    megaloblastic picture of bone marrow.
  • Increased erythrocyte precursors in bone marrow
    and decreased release into peripheral blood
    indicate ineffective erythropoiesis See
    decrease in reticulocytes.

8
Ineffective Hematopoiesis 2 of 2
  • Megaloblastic RBCs have shortened life span.
    Evidence of intramedullary hemolysis includes
    increased bilirubin, LDH (LDH1 LDH2), serum
    iron, slight ? TIBC.
  • Ineffective granulopoiesis defined by increased
    bone marrow leukocyte precursors and failure to
    release mature forms into peripheral blood.
  • Ineffective thrombopoiesis shown by presence of
    increased abnormal platelets in bone marrow and
    thrombocytopenia in peripheral blood.

9
Bone Marrow Morphology
  • Have hypercellular bone marrow.  
  • Nuclear to cytoplasm asynchrony Nucleus and
    cytoplasm mature at different rates.

10
Peripheral Blood Morphology 1 of 3
  • Macrocytic, normochromic anemia.  MCV may range
    from 100-160 fL.  MCH is elevated but MCHC is
    normal. Do NOT call megaloblastic anemia on
    basis of indices alone.
  • Hemoglobin may be low to normal.  RBC count
    usually decreased.  Leukocyte count begins as
    normal, but decreases as anemia progresses.
    Platelets also slowly decrease.
  • Peripheral smear hypocellular with presence of
    macrocytes and macro-ovalocytes. Degree of aniso
    and poik vary depending on severity of anemia.

11
Peripheral Blood Morphology 2 of 3
  • Poikilocytosis includes schistocytes, teardrops,
    spherocytes and target cells.
  • RDW is increased. May see dimorphic RBC
    populations if have iron deficiency and
    megaloblastic anemias together.
  • Red cell inclusions include Howell-Jolly bodies,
    basophilic stippling, and Cabot rings.
  • May see NRBCs.  Will have decreased reticulocyte
    count.

12
Peripheral Blood Morphology 3 of 3
  • In patients with megaloblastic anemia, life span
    of RBC is 27-75 days. Survival time of normal
    RBCs transfused to patient with untreated
    megaloblastic anemia is shortened, cause is
    unknown.
  • Hypersegmented neutrophils or multilobed
    neutrophils seen in peripheral blood. Have more
    than 5 lobes.  Are larger in size. Usually
    reported as present should give a percent value.
  • Diagnosis usually based on morphology seen on
    peripheral blood smear and other biochemical
    tests. Usually do not do bone marrow.

13
Etiologies
  • Major causes are Vitamin B12 deficiency, folic
    acid deficiency or combination of both. Can be
    in myelodysplastic syndrome, acute leukemias.
    May be drug-induced (anticonvulsants or
    chemotherapeutic drugs)

14
Vitamin B12 Deficiency Anemia
15
Sources and Requirements
  • Vitamin B12 produced by micro-organisms and
    fungi. Present in liver, fish, poultry, meat,
    eggs and dairy products. Vegetables do not
    contribute B12 to diet. Supplements available.
  • Vitamin B12 requirements increase during
    pregnancy, infancy, during growth and during
    increased metabolic states. Body stores B12 in
    liver. B12 lost through feces and urine.
  • Because the daily requirement of vitamin B12 is
    low and the storage rate is high, it takes 2-7
    years to develop Vitamin B12 deficiency as a
    result of malabsorption.

16
Transport and Metabolism
  • Two important proteins are involved in the
    transport of vitamin B12 from the duodenum to the
    ileum and from the ileum to the tissues the
    intrinsic factor (IF) and transcobalamin II

17
Causes of Vitamin B12 Deficiency
  • Deficiency progresses through four stages 
  • Stage I - negative Vitamin B12 balance
  • Stage II - B12 depletion
  • Stage III - B12 deficient erythropoiesis
  • Stage IV - B12 deficient anemia

18
Dietary Vitamin B12 Deficiency 1 of 2
  • Nutritional Vitamin B12 deficiency uncommon in
    western countries and is limited to vegetarians.
    Have an increase in plasma folate level with
    decrease in vitamin B12.
  • Newborns with B12 deficient or depleted
    B12 mothers are born B12 deficient, especially if
    breastfed. If untreated, will develop
    megaloblastic anemia. Show retarded growth and
    psychomotor development. Also have neurologic
    complications.

19
Dietary Vitamin B12 Deficiency 2 of 2
  • The major cause of vitamin B12 deficiency is
    malabsorption.
  • The most common form of malabsorption is
    pernicious anemia.
  • Other causes of vitamin B12 deficiency include
    gastrectomy, fish tapeworm, disease of ileum or
    pancreas, and drugs such as alcohol.

20
Pernicious Anemia (PA) 1 of 2
  • Most common cause of vitamin B12 deficiency.
  • Chronic disease caused by the deficiency of IF.
  • Lack of IF leads to poor B12 absorption, and,
    consequently, megaloblastic anemia.
  • Disease characterized by gastric parietal cell
    atrophy. Causes decreased secretion of intrinsic
    factor and other gastric juices.

21
Pernicious Anemia (PA) 2 of 2
  • More common in people of Scandinavian, English
    and Irish descent. More common after age 50. Is
    rare in children (congenital form).
  • Congenital pernicious anemia characterized by
    total absence of IF and normal secretion of other
    gastric juices.  Are no antibodies against IF or
    the parietal cells.

22
Pathophysiology of PA
  • Main cause PA is atrophic gastritis characterized
    by atrophy of gastric mucosa with decrease of
    gastric secretions and IF.
  • The cause of gastric atrophy is probably
    autoimmune.
  • IF is essential for absorption of vitamin B12.
  • In the absence of IF, only a small amount of
    vitamin B12 is absorbed, causing a gradual
    deficiency in vitamin B12.

23
Genetic Factors of PA
  • The congenital form of PA is inherited as an
    autosomal-recessive trait and is primarily seen
    in children before age two.

24
Immunologic Factors of PA
  • Serum of patients with PA contains autoantibodies
    to parietal cells, to IF, and to thyroid tissue.
  • Have seen association between PA and other
    autoimmune diseases.

25
Clinical Manifestations of Vitamin B12 Deficiency
  • Onset usually very gradual. Have all signs and
    symptoms of any megaloblastic anemia.
  • Fever usually present in severe anemia
  • Loss of appetite
  • Weakness
  • Glossitis (sore tongue or beefy red tongue)
  • Paresthesias
  • Bone marrow megaloblastic and see
    macro-ovalocytes in peripheral blood.
  • Associated with gastrointestinal, thrombotic,
    psychiatric, and neurologic complications

26
Neurologic Manifestations of Vitamin B12
Deficiency
  • Neurologic problems are more common in pernicious
    anemia than in other types of vitamin B12
    deficiencies.
  • Degree of neurologic involvement not related to
    severity of anemia. May be mild, moderate or
    severe. May involve degeneration of peripheral
    nerves and spinal cord.
  • In early stages, feel tingling pins and needles
    in toes and later in all four limbs, clumsiness,
    and have trouble walking.
  • Later stages involve severe weakness and
    stiffness of limbs, impairment of memory and
    depression. Severe psychiatric symptoms are
    referred to as megaloblastic madness.
  • In untreated patients, the neurologic symptoms
    are progressive.

27
Other Causes of Vitamin B12 Deficiency
  • Other causes of vitamin B12 deficiency include
  • Gastrectomy, where the IF-producing cells are
    removed.
  • Blind loop syndrome, an anatomic abnormality of
    small intestine.  Have overgrowth of bacteria in
    small bowel and the bacteria absorb all Vitamin
    B12 that is available. Corrected by giving
    tetracycline.
  • Fish tapeworm, a parasite that competes with
    vitamin B12.
  • Disease of ileum or pancreas.
  • Drugs such as alcohol.

28
Folic Acid Deficiency Anemia
29
Sources and Requirements of Folic Acid 1 of 2
  • Folic acid, also called folate, folacin or
    pteroylglutamic acid. Is water soluble vitamin.
    Concentrated in green leafy vegetables, fruits,
    dairy products, cereals, and in animal foods such
    as liver and kidney.
  • Recommended daily requirement is about 50-100 µg
    per day. Requirement dramatically increases
    during infancy, pregnancy and lactation.

30
Sources and Requirements of Folic Acid 2 of 2
  • Folate deficiency during early pregnancy can have
    adverse effects on fetus, including paralysis and
    brain damage.
  • Stored mainly in liver. Some stored in bone
    marrow and kidneys. Absorbed through duodenum
    and jejunum. Folate lost via body secretions
    such as bile, urine, sweat and saliva.
  • Takes only a few months to develop folate
    deficiency.

31
Structure of Folic Acid
  • Made of three components pteridine,
    para-aminobenzoic acid and glutamic acid.
  • Folic acid derived from diet not biologically
    active. Once absorbed, is hydrolyzed, reduced,
    and methylated to form biologically active forms.
  • Serum folate is in form methyltetrahydrofolate
    and enters all tissue cells in this form
    (CH3THF).
  • Vitamin B12 is required for folate to enter cells.

32
Causes of Folic Acid Deficiency 1 of 3
  • Main cause is dietary deficiency.  Other causes
    include malabsorption, increased requirement and
    drug-induced folate deficiencies.
  • Nutritional deficiency usually consequence of
    poverty, old age, alcoholism and chronic
    diseases.
  • Most common causes of folate malabsorption are
    tropical sprue and gluten-sensitive enteropathy.

33
Causes of Folic Acid Deficiency 2 of 3
  • Tropical sprue is infection that causes
    intestinal atrophy with clinical manifestations
    of weakness, weight loss and steatorrhea.
    Affects entire intestine and, therefore, causes
    wide variety of nutritional deficiencies,
    including Vitamin B12.  Treatment is antibiotic
    therapy.
  • Gluten-sensitive enteropathy has same clinical
    manifestations as tropical sprue. Includes both
    non-tropical sprue and childhood celiac disease.
    Affected patients cannot digest gluten, protein
    found in wheat and other grains. Severe lesions
    develop in proximal intestine.

34
Causes of Folic Acid Deficiency 3 of 3
  • Childhood celiac disease is malabsorption
    syndrome resulting in anemia caused by iron
    deficiency and to lesser degree by Vitamin B12
    and folate deficiencies.
  • Requirement for folate increases during rapid
    cellular proliferation (sickle cell anemia,
    thalassemia, spherocytosis or autoimmune
    hemolytic anemia).
  • Drug induced folate-deficient megaloblastic
    anemias been reported. Drugs include
    methotrexate, phenytoin, alcohol, oral
    contraceptives, and the antimalarial drug
    -pyrimethamine.

35
Clinical Manifestations of Folic Acid Deficiency
  • Same as those for Vitamin B12 deficiency.
  • Onset is insidious.
  • Peripheral blood and bone marrow morphology same
    as Vitamin B12 deficiency.
  • Rare to see neurologic or psychological
    abnormalities.

36
Laboratory Diagnosis and Treatment
37
Laboratory Diagnosis of Megaloblastic Anemia
  • Must consider patients physical examination,
    medical history, family history and laboratory
    tests.
  • Laboratory screening tests include Low
    hemoglobin and hematocrit, elevated MCV,
    peripheral smear evaluation (macro-ovalocytes and
    hypersegmented neutrophils).
  • Must determine exact causes of megaloblastic
    anemia.

38
Differential Diagnosis of Vitamin B12 and Folic
Acid Deficiencies
  • Figure 7-15, page 123

39
Laboratory Diagnosis of Megaloblastic Anemia
cont
  • Other tests that may support specific diagnosis
    are 
  • Antibodies to IF - present in about 50 of cases.
    Is specific for diagnosis of PA.
  • Schilling test - evaluates absorption of
    Cobalt-labeled Vitamin B12 from intestinal tract.
    Is  specific for B12. Is done to pinpoint cause
    of B12 malabsorption.

40
Treatment for Vitamin B12 Deficiency
  • Most people with a vitamin B12 deficiency require
    lifelong vitamin therapy.  Cyanocobalamin and
    hydroxocobalamin are the two therapeutic forms of
    vitamin B12 available.
  • B12 orally, injected intramuscularly or
    sub-cutaneously.

41
Treatment for Folic Acid Deficiency
  • Folic acid given daily over 2-3 week period. Is
    given orally. Life-long therapy usually not
    required.
  • May be given along with B12.

42
Response to Therapy
  • Initial sign is dramatic increase in reticulocyte
    count. May increase 50-70 initially, 5-8 days
    after beginning therapy.
  • Megaloblastic morphology of bone marrow
    disappears within first 48 hours.
  • Hematocrit returns to normal in 4-8 weeks.
  • Giant metamyelocytes and hypersegmented
    neutrophils disappear within 2 weeks.
  • Bilirubin returns to normal after 3-4 weeks.

43
Vitamin Independent Megaloblastic Changes
44
Vitamin Independent Megaloblastic Changes
  • Megaloblastic changes in peripheral blood and
    bone marrow not always caused by vitamin
    deficiency. May occur because of inherited or
    acquired predisposition, or may be drug-induced.
  • Orotic aciduria rare inherited disorder of
    pyrimidine metabolism.
  • Lesch-Nyhan syndrome X-linked disorder of purine
    metabolism.
  • Toxic materials such as arsenic can also cause
    megaloblastic anemia.

45
Macrocytic, Nonmegaloblastic Anemias
46
Macrocytic Nonmegaloblastic Anemias
  • Macrocytic anemias may be megaloblastic or
    nonmegaloblastic Must differentiate between
    them.
  • In macrocytic, normoblastic anemias, MCV is
    usually 100-110 fL In macrocytic, megaloblastic
    anemias, MCV is usually gt 110 fL.
  • Macrocytic normoblastic erythrocytes are large
    and round - not oval, and no hypersegmented
    neutrophils are present Megaloblastic RBCs are
    often ovalocytes, and hypersegmented neutrophils
    are present.
  • Exact mechanism macrocytic normoblastic anemias
    unknown. May be due to change in lipid content
    on red cell membrane or to altered maturation
    time of red cell precursors.
  • Most common causes of macrocytic nonmegaloblastic
    anemias are chronic liver disease and alcoholism.
    In most alcoholics, macrocytosis is present
    without anemia.
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