Test 4: Macrocytic Anemias Flashcards
Normoblastic, macrocytic anemia result from?
-acute blood loss or Hemolysis
-hypothyroidism
-Chronic alcohol intake
Megaloblastic, macrocytic anemia is result from…..
Ineffective hematopoiesis 
Megaloblastic anemia is the hallmark disease affecting _______ Metabolism.
DNA
What causes macrocytosis macrocytic anemia?
DNA disorders
Can also cause large granulocyte precursors (giant metamylocytes)
An abnormally large red cell precursor is called…
Megaloblast
What is the root cause of Megaloblastic anemia?
Impaired DNA synthesis (due to B12 or folate deficiency) Bad results and abnormal RBC maturation in bone marrow
What is the hemolytic component of megaloblastic anemia?
Early cell death of many RBC precursors while they are still in the bone marrow
Megaloblastic anemia affects what cells?
RBCs mostly
Also affects granulocytic and Megakaryocytic maturation but to a lesser degree
In megaloblastic anemia, Marrow is ___________ due to increased EPO but erythropoiesis is ineffective.
Hypercellular
M:E ratio is used only For what location?
Bone marrow
What is the normal M:E ratio?
2:1 4:1
____________ M:E ratio in myeloid hyperplasia or erythroid hypoplasia 
Increased
______________ M:E ratio in myeloid hypoplasia and erythroid hyperplasia
Decreased
Megaloblastic anemia:
Primary defect is inability to make the early DNA building block, _____________.
Thymidine
(DNA replication process is incomplete, Causing the cell to have nuclear growth arrest early on in mitosis when it is naturally a larger size cell)
- The resulting DNA is non-functional
In megaloblastic anemia, cytoplasmic maturation is not affected so Hgb will go and synthesis continues resulting in…..
Asynchrony
What is it called when the cytoplasm and nucleus are different stages? 
Asynchrony
Scene in megaloblastic anemia
What two nutrients can cause megaloblastic anemia?
-Vitamin B12 aka cobalamin
-folate a.k.a. folic acid
_______ is cofactor for folate conversion
B12
Why is thymidine production necessary?
It is one of the four basic nucleotides required for DNA synthesis
Folate circulates in the blood predominantly as what form?
MeTHF (inactive form)
Folic acid or B12 deficiency leads to increased levels of……
Homocystine
Folate requires vitamin B-12 to convert into ______ (Active form), Which is essential to the production of thymidine nucleotides use in DNA production.
THF
B12 metabolism:
B12 binds to _____________ (a Protein) In saliva. 
Haptocorrin
B12 metabolism:
B12 is released from ___________ in small intestine by trypsin, and then bound by _____________, a glycoprotein produced by gastric mucosa parietal cells
Haptocorrin, Intrinsic factor (IF) 
B12 metabolism:
This IF-B12 complex attaches to specific gut mucosal Receptors , is broken apart and then B12 is transferred across the gut lining.
Once in plasma, metabolically active B12 is bound to specific carrier protein, _____________.
Transcobalamin II (TC II)
B12 metabolism:
TC II Then transports B12 to the liver and bone marrow, where it is ____________ By needy cells, and B12 is then released. 
Endocytosed
Normal serum values for B12 range from ______ to _____ ng/L
200, 900
How common is vitamin B 12 deficiency?
Very rare in the US except for strict vegans
Vitamin B 12 deficiency can be due to?
-biologic competition
-Nutritional deficiency
-Malabsorption
What are examples of impaired absorption of vitamin B 12? 
-failure to separate B12 from food proteins
-failure to separate B 12 from Haptocorrin
-Lack of intrinsic factor
-Malabsorption (Celiac, surgical resection of the small bowel, tropical spur, inflammatory disease of the small intestine) 
Abnormalities of “_____________” Of intestine become overgrown with bacteria that compensate for host B12
Blind loops
A small but significant amount of folate is also a byproduct of
Normal gut flora 
Minimum daily requirement for fully is _______ Micrograms (Dietary ingestion just barely meets daily requirements) 
50
What is the main storage site of folate? How much storage is available?
Liver tissue. Only stores about three weeks worth. Deficiencies develop much quicker than B12 and folate is extensively reabsorbed and recycled
What is the reference serum values for folate?
What is RBC reference value?
5 to 21 mg/L
150 to 600 mg/L
In small intestine, Methyltetrahydrofolate (MeTHF) is made
from its dietary precursor. This MeTHF circulates through the plasma, and once inside body cells, it is converted into THF (tetrahydrofolate). What nutrient is the required cofactor for this reaction?
Vitamin B 12
Folate metabolism: 
Still in cell, THF is converted to ___________  in a rate limiting reaction, as this later molecule is converted back to DHF, thymidine is generated for DNA synthesis
5,10 methylene THF
NOTE: When MeTHF is converted to THF, the amino acid
homocysteine is also converted to methionine. If MeTHF can’t
be converted to THF (as in B12 deficiency), serum & urine
homocysteine levels increase.
______________ is an unwanted side effect of folate deficiency and about 90% of people
Hyperhomocysteinia
High risk populations for folate deficiency?
- Pregnant and lactating women
- Chemotherapy and rheumatoid arthritis patients
- Liver disease
- Anyone with B12 deficiency
- Certain chronic drug users
- Patients with chronic inflammatory bowel disease
The anti-neoplastic drug ____________ Works to kill cancer cells by blocking folate metabolism. It also blocks the Inflammation producing cytokine, TNF alpha (tumor necrosis) Which overreacts in RA
Methotrexate (MTX)
Liver disease associated with alcoholism will result in dietary folate deficiency. However, anemia of liver disease has a normal Folate, but will be ___________ w/ a ____________ marrow. 
Macrocytic, normoblastic
What is the first indication in megaloblastic anemia?
High MCV
Lab findings of megaloblastic anemia?
-High MCV
-M:E ratio is decreased (hyperactive erythroid bone marrow)
* peripheral cytopenia
-Low RBC hemoglobin and hematocrit
What is the cell morphology for megaloblastic anemia? 
Macrocytes mixed with microcytes, Aniso cytosis, Basophilic stippling, Howell jolly bodies (DNA remnants), and Cabot rings
Retics are not increased, due to ineffective hematopoiesis
Megaloblastic anemia:
Leukopenia with hyper segmented neutrophils (Called a shift to the________) 
Right
What type of homolysis is occurring in megaloblastic anemia?
Intravascular
Megaloblastic anemia:
________ haptoglobin, ___________ Serum bilirubin and LDH, and __________ Serum iron
Decreased, Increased, Increased
The megaloblastic anemia that develops specifically due to lack of intrinsic factor is called….
Pernicious anemia (PA) 
PA is ______ a dietary deficiency anemia
Not
What is the cause of pernicious anemia? 
-from autoimmune lymphocyte mediated destruction of parietal cells which causes a loss of intrinsic factor
-antibody blocking intrinsic factor binding to B12 (70%)
-Antibody directed against parietal cells in 90% of cases
_____ is the most common form of megaloblastic anemia in adults
Pernicious anemia (PA)
Symptoms of pernicious anemia?
Fatigue, shortness of breath, tingling sensations, difficulty walking, and diarrhea
What populations are At high risk for PA?
-persons of northern European descent
-Elderly (Make less stomach acid)
-Persons who inherit defective gene for intrinsic factor
-Patients with autoimmune T cell mediated parietal cell necrosis - Abs To peripheral membrane of parietal cells and provoke chronic inflammatory atrophic gastritis with pH less than 3.5
What are the symptoms for both B12 and folate deficiency‘s?
Calor, weakness, lightheadedness, dyspnea (Difficulty breathing), White jaundice and glossitis
Numbness, tingling of extremities, fine motor skills impairment, gait abnormalities, and later in disease, neurological manifestations and even megaloblastic madness that causes personality change is seen in B12 deficiency. Why?
B12 maintains myelin sheath
Why is it vital to be able to differentiate B12 front folate deficiency?
If you treat a B12 deficiency with folate, you will “cure” The peripheral blood picture, but leave the B12 deficiency to run rampant and cause permanent neurological damage
Peripheral pancytopenia Occurs in B12 or folate deficiency as it gets more severe?
Both!
MCV greater than 160 fl = 
Cold agglutinins 
 what is the normal MCH range? And what is it usually in Folate or B 12 deficiency?
26-32 Pg
> 34
In both vitamin B12 and folate deficiency anemia, granulocytes exhibit nuclear ______________
Hyper segmentation (6-10 lobes) 
RBC inclusions are always suggestive of…..
Ineffective erythropoiesis.  Seen in both folate and B 12 deficiency
What is basophilic stippling?
Ribosomal aggregates
B12 and folate deficiencies:
RPI less than two despite bone marrow hyperplasia signifies?
Inadequate bone marrow response
Howel-jolly bodies, Basophilic stippling, Cabot rings, Pilko, Teardrop cells in severe anemia Are common findings in….
B12 and folate deficiencies
Bone marrow findings in B12 and folate deficiencies…
-Usually hypercellular, Reverse ME ratio
-Many megaloblast
-Often seen with increase in my ptotic forms and with giant, immature forms of neutrophils (Usually giant bands and metamylocytes)

Are the following lab values increase or decrease in  B12 and folate deficiencies?
serum ferritin level, total serum bilirubin, LDH, urobilinogen 
All increased. Slight hemolytic anemia
Is RBC folate or tissue folate testing better?
RBC folate
(Serum B12 is relatively accurate of tissue stores)
Serum immunoassay. Such Abs Present in 70 to 90% of PA patients
Anti-IF Ab tests
If patient has decreased serum B12 in positive Anti-IF Ab test, what is the diagnosis?
Pernicious anemia
Negative result needs to be followed up with a serum gastrin assay
- Produced when
methylmalonyl CoA
accumulates and
hydrolyzes with vitamin
B12 deficiency - Also elevated in
patients with impaired
renal function (non-
specific test) - Assayed by gas
chromatography

Methylmalonic acid
Methylmalonic acid is increased in what anemia?
B12 deficiency anemia
After injection of B12 or dose of oral folate, within _____ Hours RBC precursors become normal blastic
Within ____ week, Retic count increases dramatically
24, 1
______________ means malignant or premalignant changes in Bone marrow that are morphologically similar to, but etiologically different from, megaloblastic changes. 
Megaloblastoid
Megaloblastic changes are common in malignancies of __________ cell lines. 
Myeloid
Megaloblastoid changes are characterized by:
*Pelger-Huet cells in peripheral blood, look like bilobed segs
-Left shift on WBC differential (Increase in immature wbc’s)
-Normal or increase B12 and folate levels
-Normal RBC morphology and peripheral blood (No macro ovalocytes And a normal RDW) 
Meglalobastoid refers to where?
In bone marrow
methotrexate is a vitamin B12 _________.
Antagonist
