Flashcards in Microcytic and Macrocytic Anemias (and Iron) Deck (53)
What is the common theme among megaloblastic anemias?
impairment of DNA synthesis
Describe pernicious anemia.
Deficiency of B12, which is a coenzyme needed for synthesis of thymidine; deficiency results from autoimmune gastritis - autoantibodies against gastric mucosa and impaired production of IF, resulting in impaired absorption of B12 from diet
What are four main causes of megaloblastic anemia?
- Vitamin B12 deficiency
- Folic acid deficiency
- Increased requirement
- Impaired utilization
Describe histopathologic features that are characteristic of megaloblastic anemias.
(Re: RBCs, neutrophils, & bone marrow)
macro-ovalocytes; hyperchromic or lack central pallor; MCHC not elevated; anisocytosis & poikilocytosis; reticulocyte count is low
larger than normal; show nuclear hypersegmentation
Bone marrow is hypercellular.
Why is bone marrow hyperplasia seen in megaloblastic anemia?
it's the result of increased secretion of growth factors in response to the anemia/lack of oxygen (recall: EPO from peritubular cells when they sense hypoxia)
Name two main forms of megaloblastic anemia.
1. pernicious anemia
2. folic acid deficiency
Describe the pathogenesis of pernicious anemia.
Autoimmune attack on the gastric mucosa results in chronic atrophic gastritis which is marked by a loss of parietal cells. These cells would secrete intrinsic factor (IF) but since they don't there is no absorption of B12 from diet. When B12 reserves are depleted, anemia results because DNA synthesis can't be completed without the help of B12 to make thymidine and RBCs are not replenished.
What are the 3 types of antibodies implicated in pernicious anemia?
Type I - against IF, prevents it binding B12
Type II - against cubulin; prevent uptake of B12-IF into enterocytes
Type III - bind proton pumps in gastric mucosa
What is fundic gland atrophy and what condition is it associated with?
it's an atrophy or loss of parietal and/or chief cells; it's the most characteristic finding in pernicious anemia
What are the main findings in pernicious anemia? (macroscopic signs)
- fundic gland atrophy
- atrophic glossitis
What are the CNS findings in pernicious anemia?
- demyelination of the dorsal and lateral spinal tracts
- spastic paraparesis
- sensory ataxia
- severe parasthesias in lower limbs
A diagnosis of pernicious anemia is made based on what 4 features, and is confirmed by what response?
1. mod-severe megaloblastic anemia
2. leukopenia with hypersegmented granulocytes
3. low serum Vitamin B12
4. elevated serum levels of homocysteine and methylmalonic acid
Confirm with rise in reticulocyte and hematocrit levels about5 days after administration of B12.
Describe the normal process of B12 uptake.
B12 is eaten and freed from food by pepsin in the stomach. It then associates with haptocorrin and travels to duodenum, there is it cleaved from haptocorrin by pancreatic proteases. The B12 associated with IF and this complex binds cubulin, an enterocyte surface receptor in the ileum. Once endocytosed B12 leaves IF and binds transcobalamin II. This complex is secreted into the plasma. Via plasma it can get to GI tract or Bone marrow where it's needed for DNA synthesis of rapidly dividing cells.
Describe anemia of folate deficiency.
folic acid is needed to carry out carbon transfers for the following reactions:
-conversion of homocysteine to methionine
Being unable to carry out any of these reactions means that you can make thymidine and that will halt DNA synthesis, resulting in megaloblastic anemia.
How can diagnosis of folate deficiency be made?
measure decreased folate levels in the serum or RBCs; also there must be no neurologic symptoms as that is unique to B12 deficiency (in cases of anemia)
Why is it important to differentially diagnose B12 deficiency versus folate deficiency in an anemic patient?
Because the treatments have a major difference:
B12 deficiency can cause CNS symptoms. Administration of folate will improve anemia of folate deficiency, but it will make the neuro symptoms worse in B12 deficiency.
Iron deficiency impairs the synthesis of what important RBC component?
hemoglobin - since iron is required to synthesize Hgb
Describe the absorption, transport, utilization, and storage process of iron.
Iron is absorbed from food either as heme iron or as nonheme iron--nonheme iron must be reduced then uptaken by DMT-1 transporter and oxidized. It then is secreted into plasma by ferroportin (regulated by hepcidin).
Transported in plasma bound to transferrin (synthesized in liver).
Delivered by transferrin to the bone marrow for synthesis of Hgb for RBCs, or the liver for storage in hepatocytes.
Stored as bound to either ferritin or hemosiderin in the hepatocytes, or in macrophages in spleen, bone marrow, or skeletal muscle. Gets into macrophages via breakdown of RBCs.
What is the chemical basis of the Prussian-blue stain?
iron in hemosiderin is chemically reactive and turns blue-black when exposed to potassium ferrocyanide. Used to observe Fe stores within liver macrophages and hepatocytes.
What is hepcidin and what does it do?
A small circulating peptide that is synthesized and released from the liver in response to increased intrahepatic iron levels. It binds to and causes the endocytosis (downregulation) of ferroportin, and when that happens less iron is absorbed and rather sequestered in the enterocytes.
*Released in response to having enough iron in storage.
What enzymes are responsible for luminal reduction of iron? Which are responsible for intracellular oxidation of iron?
ferrireductases: cytochrome b, STEAP3
ferrioxidases: hephaestin, ceruloplasmin
What are 4 possible causes of iron deficiency?
1. dietary lack
2. impaired absorption
3. increased requirement
4. chronic blood loss
*chronic blood loss is the most common cause in the western world
Which is more absorbable: heme iron or inorganic iron?
Describe the histopathology of iron deficiency anemia.
-hypochromic microcytic anemia (on peripheral blood smear)
-disappearance of stainable iron from macrophages in the bone marrow (see on Prussian blue stain)
Loss of iron from CNS may lead to what?
pica (eating non-food items)
Describe blood levels in iron deficiency anemia.
-depressed Hct and Hgb
-low serum iron and ferritin
-high TPIBC (reflecting elevated transferrin levels)
-decreased serum hepcidin
What is a possible treatment for [uncomplicated] iron deficiency?
oral iron supplements
Describe anemia of chronic disease.
stems from reduced proliferation of RBCs and impaired iron use.
Can be caused by microbial infections (sequester iron so bacteria don't get to use it); chronic immune disorders; neoplasms
What is the most appropriate treatment for anemia of chronic disease?
treatment of the underlying condition