Anemia: Diminished Erythropoiesis Flashcards
Normal bone marrow
Describe the process of Vit B12 absorption
binding globulin + Vit B12 → haptocorrin transports to duodenum → IF transports to SI where it is absorbed into blood stream → transcobalamin II picks it up
Megaloblastic anemia (bone marrow aspirate). A to C, Megaloblasts in various stages of differentiation. Note that the orthochromatic megaloblast (B) is hemoglobinized (as revealed by cytoplasmic color), but in contrast to normal orthochromatic normoblasts, the nucleus is not pyknotic. The early erythroid precursors (A and C) and the granulocytic precursors are also large and have abnormally immature chromatin.
Most important cause of anemia from inadequate production of RBC
nutritional deficiency
(secondary to renal failure or chronic inflammation)
Anemia due to inadequate RBC production: less common causes
generalized bone marrow failure → aplastic anemia, primary hematopoietic neoplasms, infiltrative disorders (bone marrow replacement)
6 extrinsic causes of anemia (decreased production of RBC)
- Nutritional deficiency
- EPO deficiency (ex: renal failure)
- Immune-mediated
- Inflammation → iron sequestered
- Infections of RBC precursors
- Neoplasm, marrow lesion
What is an example of an intrinsic cause of decreased RBC production?
Fanconi anemia (stem cell depletion)
(other causes of intrinsic = hereditary. i.e. genetic defect in RBC maturation or stem cell depletion)
Vitamin B12 & B9 (folate) are important coenzymes in the synthesis of _____. Deficiency → ______.
- thymidine (DNA base)
- deranged or inadequate DNA synthesis = defective nuclear maturation
Megaloblastic anemia has many causes related to impaired DNA synthesis → ineffective hematopoiesis & morphological changes (large erythroid precursors / RBCs). What are the 2 main causes?
- B12 deficiency → pernicious anemia
- B9 deficiency → folate deficiency anemia
2 Causes of pernicious anemia
- inadequate diet/vegetarianism
- impaired absorption (IF deficiency)
5 Causes of folate deficiency anemia
- inadequate diet/alcoholism
- impaired absorption
- infancy
- pregnancy
- Rx: anticonvulsants, oral contraceptives, folic acid antagonist
_______ is a morphologic feature seen in all megaloblastic anemias.
macro-ovalocytes: macrocytic, oval RBCs that are larger than normal and have ample hemoglobin
(lack central pallor; appear hyperchromic w/o elevated MCHC)
Decreased reticulocytes → nucleated RBC progenitors are seen in severe ______.
anemia (decreased production)
(if they are increased → blood loss)
Hypercellular red marrow (marrow hyperplasia) is a response to _______
increased growth factors (like EPO)
(most precursors are deranged → apoptosis; megaloblastic anemia)
Pancytopenia
decreased number of all cell lines in peripheral blood
How does pancytopenia develop in macrocytic anemia?
increased levels of EPO → marrow hyperplasia, but DNA is deranged → apoptosis
Pernicious anemia caused by vit B12 deficiency. Most common cause :
autoimmune gastritis → decreased IF production
(i.e. chronic atrophic gastritis)
Where do humans get Vit B12 (aka cobalamin)?
Animal products
(stored in the liver)
2 major biochemical functions of Vit B12 (cobalamin)
- DNA synthesis
- Odd-chain FA metabolism
What is the role of Vit B12 in DNA synthesis
methylcobalamin = cofactor in converting homocysteine → methionine
What is the role of Vit B12 in odd chain FA synthesis?
Propionyl CoA → methylmalonyl CoA by methylmalonyl CoA mutase + vitamin B12 (cofactor)
Why does Vit B12 deficiency manifest as neurologic deficits?
Increase in propionyl CoA → replaces acetyl CoA in neuronal membranes→ demyelination
The clinical features of pernicious anemia include: onset ~ 60 y.o. and _____ (4)
- megaloblastic anemia
- leukopenia w/hypersegmented neutrophils
- decreased serum vitamin B12
- increased homocysteine/methylmalonic acid
Diagnosis of pernicious anemia is via ______.
parenteral administration of Vit B12 → 5 days later measure reticulocytes & high hematocrit
Atrophy of metaplasia seen in pernicious anemia increases the risk of ______
carcinoma
Patients with pernicious anemia may and anti-_______ antibodies in their serum.
intrinsic factor (IF)
Why are patients with pernicious anemia at an increased risk for atherosclerosis?
increased homocysteine levels
3 primary types of autoimmune attack on gastric mucosa seen in pernicious anemia
- type I antibody: block B12 binding to IF
- type II antibody: prevents binding of B12-IF to ileal receptor
- type III antibody: against alpha/beta subunits of gastric proton pump in parietal cells
Primary cause for gastric pathology → pernicious anemia
auto-reactive T cells responding to gastric mucosa
(associated w/other autoimmune disorders; such as autoimmune thyroiditis & adrenalitis)
Pernicious anemia: tx
parenteral or high-dose oral vit B12
(anemia/neurologic changes cured, but damage to gastric mucosa remains → increased risk of carcinoma
Pernicious anemia also has macro-ovalocytes. What are 3 other findings?
- fundic gastric cell atrophy: ⇣ chief & parietal cells
- intestinalization: glandular epithelium → metaplasia
- atrophic glossitis: shiny, glazed & “beefy”
- CNS lesions: dorsal/lateral spinal tracts
the one to the right
Anemia of folate deficiency is mainly due to ______
suppression of DNA synthesis
2 major causes of folic acid deficiency
- increased requirements (pregnancy)
- decreased intake or absorption
Humans depend solely on ______ sources of folic acid.
dietary: green veggies, fruit, animal livers
What are the causes of decreased absorption of folic acid (2)?
- alcohol consumption (cirrhosis traps folic acid)
- meds: phenytoin & oral contraceptives
What are the causes of increased requirement of folic acid that may lead to deficiency?
- pregnancy
- infancy
- cancer
- hemolytic anemia (hyper-hematopoesis)
How does methotrexate impair folic acid utilization?
inhibits dihydrofolate reductase → FH4 deficiency
Folic acid derivatives act as intermediates in the transfer of one carbon-units such as formyl & methyl in which functions?
- purine synthesis
- homocysteine conversion to methionine (also requires methylcobalamin; B12)
- dUMP → dTMP (DNA synthesis)
How do you distinguish between B12 & B9 deficiency since both cause megaloblastic anemia (2)?
- Folate deficiency does not cause neurologic changes
- they also both have increased serum homocysteine, but folate deficiency has normal methylmalonate levels
B12 deficiency will respond to Folate tx, but this will not prevent ______ in B12 deficiency.
neurologic symptoms
Most common nutritional deficiency in the world
iron deficiency anemia → inadequate hemoglobin synthesis
Dietary iron typically comes from _______
animal sources of hemoglobin
80 % of functional iron is used for _______
hemoglobin
________ levels correlate well with body iron stores → serum ferritin = good test for iron deficiency.
Plasma ferritin
Iron storage pool = _________ (2) in the liver and mononuclear phagocytes.
hemosiderin and ferritin
Free iron is highly toxic. It must be sequestered by binding to ________ or ______.
- ferritin
- hemosiderin
Hepatocyte iron is from ______.
plasma transferrin
Storage iron is in ________.
macrophages that have broken down RBCs
(partially degraded as hemosiderin granules)
What can you stain with Prussian blue stain that indicates iron overload?
hemosiderin iron
(normal iron stores should only have a little bit)
Iron stores are maintained by regulating ______, but there is no mechanism for regulating ______.
- absorption of dietary iron from the proximal duodenum
- iron excretion
(iron is very toxic, but req. for cellular fxn → tight regulation)
_______ must convert non-heme iron (Fe3+ ; ferric) must be → ferrous (Fe2+) in order to be absorbed from the gut.
Ferrireductases
Once the ferrireductase has converted ferric iron to ferrous iron it is transported by _____.
DMT1
Very little dietary non-heme iron is absorbed; by contrast _____ of heme iron from animal protein is absorbed.
25%
2 possible pathways once iron is absorbed from the GI :
- transport to blood (via ferroportin)
- storage as GI mucosal iron
Define Hepcidin
Blood peptide made by liver when there is an increase in intrahepatic iron
Hepcidin inhibits iron by _______
binding ferroportin
(inhibits MF release & traps it in duodenal cells as mucosal ferritin)
It is known as ______ when hepcidin binds ferroportin and traps iron in the duodenal enterocytes.
mucosal ferritin
(this is lost when mucosal cells are sloughed)
MF iron is typically used for _______.
hemoglobin synthesis by RBC precursors
The body requires absorption of ____ of dietary iron/day.
1 mg
(only 10-15% ingested iron absorbed)
Which populations lack dietary iron
- infants (little in cow or breastmilk)
- elderly
- impoverished
Causes of impaired iron absorption
- sprue (enteritis)
- fat malabsorption (steatorrhea)
- chronic diarrhea
- gastrectomy → decreased acidity of proximal duodenum (acidity help uptake)
Populations with increased iron dietary requirements
- growing children (infant-adolescent)
- pregnancy
MCC of iron deficiency anemia
chronic blood loss
(external or internal bleeding)
Sites of internal bleeding that can lead to iron deficiency anemia (3)
- GI
- urinary
- genital tracts
(always assume GI blood loss until proven otherwise)
In the early stages of hypochromic microcytic anemia, _____ will increase
bone marrow erythropoiesis
(at first ferritin/hemosiderin stores will maintain Hgb/Hct)
Hypochromic microcytic anemia will only appear when ______.
iron stores are depleted
Iron deficiency anemia is mainly due to ______ (3) causes.
- pregnancy
- GI disease
- malnutrition
Depletion of iron-containing enzymes → _____ (s/sx)
- koilonychia (“spoon nails”)
- alopecia
- atrophy of tongue/GI
- intestinal malabsorption
Why do patients with iron deficiency anemia crave eating dirt (or flour or clay)?
they need the iron (Pica)
Plummer-Vinson Syndrome (rare iron-deficiency disease) classic triad
- esophageal webs
- microcytic hypochromic anemia
- atrophic glossitis
- hypochromic microcytic anemia
- blue circle = normal RBCs; fully hemoglobinized
define esophageal web (as seen in Plummer-Vinson syndrome)
dysphagia for solids but not liquids
In iron deficiency anemia the bone marrow aspirate will reveal ______ (2).
- Moderate increase in erythroid progenitors
- Disappearance of stainable iron from macrophages
In iron deficiency anemia the peripheral blood smear will show which important finding?
pencil cells: poikilocytosis (small, elongated red cells)
In addition to low hemoglobin and low hematocrit, lab findings for iron deficiency anemia include ______
- ⇣ serum iron
- ⇣ serum ferritin
- ⇡ iron-binding capacity (iron binding proteins empty)
- ⇣ iron stores → decreased hepcidin serum levels
Iron deficiency anemia: tx
oral iron supplementation
