Disorders of DNA Met and Bone Marrow Failure

Question 1

Megaloblastic Anemia

Answer 1

• Impaired DNA synthesis
• Normal RNA synthesis
• Megaloblastic changes noted in ALL hematopoietic lines
• Nuclear - cytoplasmic asynchrony

Question 2

Vitamin B12 / Folate

Answer 2

• coverts uridine to thymidine (needed for DNA synthesis)
• converts homocysteine to methione (needed for nervous system function)
• converts methylmalonic acid to succinyl CoA (needed for myelin sheath formation)
• Vit B12 keeps folate in cell via Methyl folate trap

Question 3

Ineffective Erythropoiesis in megaloblastic anemia

Answer 3

• Increased Pre-RBC in Bone Marrow, with decreased release into peripheral blood. (RBC so abnomal they don’t make it into the peripheral blood)
• Intramedullary hemolysis (breaking up of RBC in bone marrow):
• • Increased serum bilirubin, LDH, and Iron
• Ineffective granulopoiesis (giant metas and bands die prematurely in marrow)
• Ineffective thrombopoieisis (increased abnormal megakaryotcytes (platelet precursors) in marrow + thrombocytopenia)

Question 4

Bone marrow morphology in megaloblastic anemia

Answer 4

• Hypercellular
• M:E Ratio is increased (1:1)
• Megaloblastic erythroid precursors
• Megaloblastic WBC precursors
• Megaloblastic megakaryocytes
• ** Nucleus looks like salami

Question 5

Peripheral blood morphology in megaloblastic anemia

Answer 5

• Macrocytosis (Increased MCV)
• Macroovalocytes
• Pancytopenia (all cells decreased)
• Decreased reticulocytes
• Howell Jolly Bodies (nuclear fragment)
• Nucleated RBC
• Hypersegmented neutrophils (> 5)

Question 6

Causes of megaloblastic anemia

Answer 6

• Vitamin B12 Deficiency
• Folic Acid Deficiency
• Myelodysplastic Syndromes / Leukemia
• Drug-induced: Chemotherapy, Anticonvulsants

Question 7

Vitamin B12 Metabolism

Answer 7

• B-12/IF complex travels down to ileum, where it binds to specific receptor.
• In ileal cell, B12 is bound to transcobalamin II, and released into portal circulation.
• TCII/B12 complex circulates, and is taken up by cells, where B12 is released.
• Complex in blood is transferred to TC I.

Question 8

Vitamin B12 Deficiency

Answer 8

• only from animal cells
• 2-7 year storage = daily requirement low and storage rate high
• parietal cells (stomach) secrete IF - intrinsic factor
• IF binds to B-12 at higher pH in duodenum

Question 9

Causes of B12 Deficiency

Important Concept

Answer 9

• Poor intake (rare)
• Lack of IF production
• Gastrectomy, Pernicious Anemia
• B12/IF complex can’t get to terminal ileum
• Bacterial overgrowth, tapeworm
• Complex can’t be absorbed
• No ileum, sprue, Crohn’s disease
• Transcobalamin deficiency (very rare)

Question 10

Pernicious Anemia

Answer 10

• autoimmune disease of late middle age
• most common cause of cobalamin deficiency
• 2% of people over 60 have this disease
• seen more in norther europeans and african americans
• Can be Autosomal Recessive
• Gastric parietal atrophy:
• • Achlorhydria, no IF production
• • Antibodies against parietal cells and IF

Question 11

Clinical Manifestations of Pernicious Anemia

Answer 11

• loss of appetite
• glossitis (smooth tongue)
• neurologic problems

Question 12

Folate Metabolism

Answer 12

• Folate present in green leafy vegetables.
• Absorbed in small intestines.
• Body has only 3-6 month store of folate.
• Folate absorbed in small bowel, transported and stored in liver.
• Some folate excreted in bile, then reabsorbed.
• Alcoholism reduces reabsorption

Question 13

Causes of Folic Acid Deficiency

Important Concept

Answer 13

• Main cause is decreased dietary intake
• Malabsorption (ex. Tropical sprue)
• Increased requirement: Pregnancy, Increased hematopoiesis (growth spurt in children)
• Drug-induced
• *Low Vit B12 = Low RBC Folate lvls

Question 14

Macrocytosis

Important Concept

Answer 14

• MCV > 100 fL, but usually not > 110 fL
• RBC appear large and round
• Causes include:
• • increased cholesterol and/or lipid in RBC membrane
• • anemia associated with an increased reticulocyte count

Question 15

Causes for Macrocytosis

Important Concept

Answer 15

• Alcoholism
• Chronic liver disease
• Shift reticulocytosis (lots of retics = polychromasia)
• Hypothyroidism
• Hematologic disorders
• Immunosuppressive drugs (AZT)

Question 16

Aplastic Anemia

Important Concept

Answer 16

• Disorder characterized by loss or replacement of bone marrow elements
• May be hereditary or acquired (more common)

Question 17

Acquired Aplastic Anemia

Answer 17

• Idiopathic - 70% of cases
• Chemical exposure: Benzene compounds, insecticides, weed killers; May be reversible, also associated with chromosomal abnormalities
• Drugs (Ex. Chloroamphenicol and phenylbutazone)
• Radiation (Production of free radicals interferes with DNA production)
• Infections (Predominantly viral)
• Autoimmune (Usually a result of altered immune status; Pregnancy, graft vs host)

Question 18

Congenital Aplastic Anemia

Answer 18

Fanconi’s Anemia

• Autosomal recessive
• Associated with physical and chromosomal abnormalities
• Patients have an increased incidence of cancer and leukemia
• Currently, most patients are treated with allogeneic bone marrow transplant.

Question 19

Clinical Manifestations of Aplastic Anemia

Answer 19

• Pancytopenia (overall shut down of bone marrow)
• Fatigue, dyspnea, palpitations
• Bleeding
• Infection

Question 20

Laboratory Evaluation of Aplastic Anemia

Answer 20

• Pancytopenia
• Normochromic, normocytic anemia of varying degrees
• Decreased reticulocyte***
• Hypocellular marrow

Question 21

Treatment and Prognosis of Aplastic Anemia

Answer 21

• Untreated, poor prognosis
• 1970 - Androgen therapy to stimulate erythropoiesis (Testosterone stimulates RBC production), slowed progession of disease
• Bone marrow transplant – 75% long term survival
• Gene therapy – in developmental stages

Question 22

Pure Red Cell Aplasia

Important Concept

Answer 22

• Rare
• Selective hypoproliferation of the unipotential erythroid stem cell (still aplastic buy only effects RBCs)
• Acquired (Acute or Chronic): About 80% have spontaneous remission
• Congenital - Diamond-Blackfan Syndrome

Question 23

Acquired Pure Red Cell Aplasia

Answer 23

• Viral: Temporary erythroblastopenia of childhood (TEC), Parvovirus B19
• Subsequent to hemolytic anemias
• Drugs and chemicals

Question 24

Chronic Pure Red Cell Aplasia

Answer 24

• Autoimmune disorders: Lupus, Rheumatoid arthritis, Autoimmune hemolytic anemia
• Neoplasms
• Drugs

Question 25

Diamond-Blackfan Syndrome

Answer 25

• Rare, congenital disorder
• Presents from infancy to 6 years of age
• No leukopenia or thrombocytopenia
• Erythropoietin is normal or increased
• Most likely problem is a molecular defect leading to decreased responsiveness to erythropoietin
• Associated with increased incidence of AML

Question 26

Congenital Dyserythropoietic Disorders

Answer 26

CDAs

• associated with anemia, erythroid hyperplasia, and weird/abnormal erythroid precursors (often multinucleated)
• Type I, II (most common) and III