Anemias of Diminished Erythropoesis

Question 1

Diminished Erythropoiesis

Answer 1

Inadequate supply of substances needed for hematopoiesis
-Iron, folic acid, vitamin B12
Bone marrow failure
Bone marrow replacement

Question 2

Iron Metabolism

Total body iron content

Answer 2

2 gm for women, up to 6 gm for men
80% functional iron, 20% storage pool
-Functional iron
*80% hemoglobin
*20% myoglobin and other iron containing proteins (catalase, cytochromes)
-Storage pool
*Hemosiderin and ferritin
*Stored iron mainly in liver, spleen, marrow, skeletal muscle

Question 3

Iron laboratory tests

Answer 3

Serum ferritin
-Assesses body iron stores
-Stainable iron in marrow can also be used
Serum iron levels (nl: 100 µg/dL)
Total iron binding capacity (TIBC) (nl: 300 µg/dL)
-Measure of transferrin levels
% saturation or transferrin % saturation (nl: 33%)
-Serum iron/TIBC

Question 4

Iron Metabolism

Answer 4

Metabolic pathways are strongly biased toward iron retention
No regulated pathway for iron excretion
-Normal losses are 1-2 mg/day
Iron balance is maintained by regulating iron absorption

Question 5

Iron Dietary forms

Answer 5

Heme iron from animal products
-About 20% is absorbable
Inorganic iron in vegetables
-1-2% is absorbable

Question 6

Iron absorbtion

Answer 6

Iron is absorbed in the duodenum

Iron passes through the apical membrane then the basolateral membrane of enterocytes

Question 7

Nonheme iron

Answer 7

Apical membrane
-Ferric reductase reduces iron
-Divalent metal transporter (DMT1) transports across apical membrane to cytoplasm
Basolateral transfer of iron to transferrin in plasma
-Ferroportin transport protein
-Hephaestin oxidizes iron
Iron not transported to plasma is stored as ferritin and lost though exfoliation of mucosal cells

Question 8

hepcidin

Answer 8

Iron balance is regulated by a small hepatic peptide, hepcidin

• Hepcidin binds to ferroportin and causes it to be internalized and degraded
• High hepcidin results in reduced iron absorption
• Low hepcidin results in higher iron absorption

Question 9

Iron Deficiency Anemia Causes

Answer 9

Most common type of anemia
Causes
Low dietary intake
-Rarely cause in US where average iron intake is 10-20 mg/day
-Important cause in other parts of world where low intake is combined with poor bioavailability of predominantly vegetarian diet
Malabsorption
-Sprue, celiac disease, gastrectomy
Increased demands
-Pregnancy, infancy
Chronic blood loss
-Most important cause in Western world
-GI tract (e.g., ulcers, colon cancer, hemorrhoids, hookworm)
-Female genital tract (e.g., menorrhagia, cancers)

Question 10

Iron deficiency develops insidiously

Answer 10

Iron stores depleted
Decline in serum ferritin; loss of stainable iron in marrow
Decrease in serum iron and rise in TIBC
Ability to synthesize iron containing proteins diminished

Question 11

Iron Deficiency Anemia morphology

Answer 11

Anemia is generally mild
Microcytic and hypochromic (↓MCV and ↓MCHC)
Increased platelet count

Question 12

Iron Deficiency Anemia clinical

Answer 12

Mostly asymptomatic or non-specific
-Weakness, listlessness
In severe cases
-Pallor, koilonychia (nail spooning), alopecia, atrophy of tongue and gastric mucosa, intestinal malabsorption
-Pica, consuming non-foodstuffs like dirt or clay
In well-nourished persons, iron deficiency anemia is not a disease but a symptom of an underlying disorder

Question 13

Anemia of Chronic Disease

Answer 13

Most common form of anemia in hospitalized patients
Resembles iron deficiency anemia, but is caused by inflammation-induced iron sequestration within the mononuclear phagocyte system

Question 14

Anemia of Chronic Disease

Seen in chronic inflammatory disorders

Answer 14

Chronic microbial infections
-Osteomyelitis, bacterial endocarditis, lung abscess
Chronic immune disorders
-Rheumatoid arthritis, regional enteritis
Neoplasms
-Carcinoma of lung and breast, Hodgkin lymphoma

Question 15

Anemia of Chronic Disease anemia

Answer 15

Normocytic/normochromic most commonly

Microcytic/hypochromic

Question 16

Anemia of Chronic Disease labs

Answer 16

Low serum iron
High serum ferritin or marrow iron
Low TIBC
These R/O iron deficiency

Question 17

Anemia of Chronic Disease

Answer 17

Findings due to high levels of hepcidin
Elevated hepcidin caused by proinflammatory cytokines
Inflammation also blunts erythropoietin response
Only effective treatment of the underlying disease is curative
-Iron and epo treatment may improve anemia

Question 18

Megaloblastic Anemia causes

Answer 18

Folic acid deficiency and vitamin B12 deficiency

Caused by impaired DNA synthesis

Question 19

Megaloblastic Anemia CBC

Answer 19

Macrocytic anemia
-↑MCV often >110 fl
Granulocytopenia
Thrombocytopenia

Question 20

Megaloblastic Anemia Peripheral blood morphology

Answer 20

Abnormally large red cells (macrocytes or ovalomacrocytes)
Hypersegmented neutrophils (seen before anemia develops)

Question 21

Megaloblastic Anemia marrow morphology

Answer 21

Enlarged erythroid precursors (megaloblasts)
Enlarged granulocytic precursors (giant metamyelocytes)
Megakaryocytes may be enlarged with abnormal nuclei

Question 22

Megaloblastic Anemia

Answer 22

Impaired DNA synthesis results in delayed nuclear maturation and cell division
Synthesis of RNA and cytoplasmic elements proceeds at normal rate
Cells show nuclear-cytoplasmic asynchrony

Question 23

Megaloblastic Anemia contin

Answer 23

Impaired DNA synthesis causes anemia
-Some megaloblasts undergo apoptosis due to the DNA synthesis defect (ineffective hematopoiesis)
-Other cells mature but with fewer cell divisions
*Lower total output of cells from a precursor cell
Granulocyte and platelet lineages are similarly affected
Pancytopenia rather than isolated anemia

Question 24

Folic Acid Deficiency Anemia Risk factors

Answer 24

Marginal folate stores are fairly common
Poor diet
Increased needs
-Pregnancy, chronic hemolysis
Poor absorption (upper third of small intestine)
-Phenytoin, oral contraceptives
-Malabsorptive disorders
Inhibitors of folate metabolism (methotrexate)

Question 25

Folic Acid Deficiency Anemia Clinical

Answer 25

Onset is insidious May be complicated by other coexisting vitamin deficiencies GI tract symptoms -Sore tongue, cheilosis

Question 26

Folic Acid Deficiency Anemia Diagnosis

Answer 26

Peripheral blood and bone marrow examination Serum and red cell folate levels Vitamin B12 level

Question 27

Vitamin B12 (Cobalamin) Deficiency Anemia

Answer 27

Causes a megaloblastic macrocytic anemia similar to folate deficiency Causes a demyelinating disorder involving the spinal cord Many causes of vitamin B12 deficiency -Long-standing malabsorption is the most common and important -Liver stores are normally last more than 5 years

Question 28

Vitamin B12 (Cobalamin) Deficiency Anemia Pernicious anemia

Answer 28

Presumed cause of vitamin B12 deficiency until proven otherwise in the western world Autoimmune reaction against parietal cells and intrinsic factor Antibodies present in the serum and gastric juice of most patients -Parietal canalicular antibodies -Blocking antibodies prevent B12-IF binding -Binding antibodies prevent binding to ileal receptor Association with other autoimmune diseases -Hashimoto thyroiditis, Addison disease, type I diabetes

Question 29

Vitamin B12 (Cobalamin) Deficiency Anemia Subacute combined degeneration

Answer 29

Demyelination of the posterior and lateral columns of the spinal cord Severity of neurological problems not related to degree of anemia Can see neurological disease in absence of anemia

Question 30

Vitamin B12 (Cobalamin) Deficiency Anemia Clinical

Answer 30

Non-specific anemia symptoms GI symptoms similar to folate deficiency Spinal cord disease -Symmetric numbness, tingling, and burning in hands or feet -Unsteady gait -Loss of position sense, especially in toes Increased risk of gastric carcinoma with pernicious anemia

Question 31

``` Vitamin B12 (Cobalamin) Deficiency Diagnostic features of pernicious anemia Anemia ```

Answer 31

Low serum vitamin B12 levels Normal or elevated folate levels Serum antibodies to intrinsic factor Moderate to severe megaloblastic anemia Leukopenia with hypersegmented neutrophils Dramatic reticulocyte response (in 2-3 days) to parenteral vitamin B12

Question 32

Warning

Answer 32

Vitamin B12 deficiency anemia will respond to folate therapy! This will only fix the anemia; the neurological problems will persist and progress

Question 33

Aplastic Anemia

Answer 33

Multipotential myeloid stem cells are suppressed leading to marrow failure and pancytopenia Idiopathic >50% of the time Exposure to myelotoxic agents in remainder -Can group the exposures *Damage is predictable, dose related, and usually reversible Antineoplastic drugs, benzene, chloramphenicol *Idiosyncratic or hypersensitivity reactions to small doses Known toxic: Chloramphenicol Not toxic: Sulfonamides

Question 34

Aplastic Anemia | Some cases arise after certain viral infections

Answer 34

Community-acquired viral hepatitis - Non-A, non-B, non-C virus - Aplasia develops several months after hepatitis resolves

Question 35

Aplastic Anemia Idiopathic

Answer 35

Autoreactive T cells may play a role -70-80% respond to immunosuppressive therapy aimed at T cells -Association with Paroxysmal Nocturnal Hemoglobinuria *Is PGI anchor the target of the T cells? Telomerase defects in small fraction

Question 36

Aplastic Anemia Morphology

Answer 36

``` Hypocellular marrow (<10% cellularity) Only lymphocytes and plasma cells present “Dry tap” Pancytopenia -Normocytic/normochromic anemia -Decreased reticulocytes ```

Question 37

Aplastic Anemia Clinical

Answer 37

Anemia: weakness, listless, pallor, dyspnea Thrombocytopenia: petechiae, ecchymoses Granulocytopenia: infections Splenomegaly is absent

Question 38

Aplastic Anemia | Idiopathic form has poor prognosis if untreated

Answer 38

Bone marrow transplant -Young, non-transfused patients Immunosuppressive therapy

Question 39

Myelophthisic Anemia

Answer 39

Extensive replacement of the bone marrow by tumors or other lesions Metastatic breast, lung, or prostate cancer Other cancers Advanced tuberculosis Lipid storage disorders Osteosclerosis

Question 40

Myelophthisic Anemia Morphology

Answer 40

Anemia and thrombocytopenia principally -White cells less effected Misshapen red cells (esp. teardrops) Immature granulocytic and erythroid precursors (leukoerythroblastosis) Treatment is to manage underlying condition

Question 41

Polycythemia

Answer 41

Polycythemia or erythrocytosis is the increase in the blood concentration of red cells Usually correlates with an increased hemoglobin concentration

Question 42

Relative Polycythemia

Answer 42

Hemoconcentration due to decreased plasma volume - Any cause of dehydration - Water deprivation, prolonged vomiting, diarrhea, excessive use of diuretics

Question 43

Absolute Polycythemia

Answer 43

``` Increase in total red cell mass Primary -Autonomous proliferation of myeloid stem cells Secondary -Response to increased erythropoietin -Appropriate *Lung disease, high-altitude living, cyanotic heart disease -Inappropriate *Erythropoietin-secreting tumors, doping ```