What are the characteristic lab findings of hypoproliferative anemias?
Anemia and low reticulocyte count in lab
What are the types of hypocellular bone marrow/hypercellular bone marrow?
Hypocellular bone marrows
- Stem cell disorders
Hypercellular bone marrows
- Ineffective erythropoiesis
What should the differential for pancytopenia be?
Stem cell disorders – Aplastic anemia, PNH
Ineffective hematopoiesis – MDS, Megaloblastic anemia
Marrow infiltration – Leukemia/lymphoma, metastatic carcinoma, myelofibrosis
Splenic sequestration – Massive splenomegaly
Drugs/Treatments – Immunosuppressants, Chemotherapy/radiation, other medications
What is associated with hypersplenism?
Variable cytopenias – Estimated that 1/3 of platelets are stored in spleen
What are the major steps involved in the folate pathway?
Conversion of dUMP to dTMP
One carbon for S-adenosylmethionine
How is folate activated? What is it inhibited by?
Takes folate which is activated to THF via DHF reductase
Inhibited by MTX
What does thymidylate synthetase do?
What inhibits it?
What does it require?
Conversion of dUMP to dTMP
Inhibited by 5-FU derivative FdUMP
What are potential etiologies of megaloblastic anemia?
DHF reductase deficiency via MTX
Thymidylate synthetase deficiency – 5FU
Vitamin B12 deficiency
What is the prurpose of the folate one-carbon?
What is it required for?
Required for thymidylate synthetase for conversion of dUMP to dTMP for DNA synthesis
Synthesis of methionine for SAM
What is 5-Adenosylmethionine used for?
Methyl donation via methyl transferases
What does methionine synthetase require?
Requires methyl THF and Vitamin B12
What is Vitamin B12 bound to and how is it taken and transferred?
Bound to food
Released in stomach by HCl and pepsin
Binds mainly to R-protein but some to IF
In duodenum, R-protein degraded releasing Vitamin B12
Vitamin B12 binds intrinsic factor
Complex binds IF receptor
Vitamin B12 transferred to transcobalamin
What are the causes of vitamin B12 deficiency?
Increased requirement (Pregnancy)
Decreased intake (strict vegans)
Tapeworm – Diphyllobothrium latum
What are the clinical manifestations of Vitamin B12?
Megaloblastic anemia, pernicious anemia
Subacute combined degeneration
Dorsal and lateral tract demyelination
What is pernicious anemia? What is its etiology?
Secondary B12 def to IF abnormalities
Most frequent cause of B12 deficiency
Autoantibodies against IF – Required for diagnosis
What are the lab values of vitamin B12?
Low vitamin B12 levels
Low reticulocyte count
Auto-antibodies to IF or parietal cells (if pernicious anemia)
Elevated methylmalonic acid
What are the causes of folate deficiency?
Decreased intake – Alcoholism, poverty
Increased requirements – Growth, pregnancy, high cell turnover: hemolytic anemias, leukemias
Defective absorption – Jejunal resection or malabsorption
Folic acid antagonists
What are the clinical manifestations of folate deficiency?
Neural tube defects
Spina bifida occulta – Anencephaly
Importance of supplementation
What is the therapy for megaloblastic anemia?
Vitamin B12 or folate supplementation
Oral vs IM injection
Do not treat vitamin B12 deficiency with folate
Anemia will reverse
Neurological manifestations will not
What are the diagnostics for megaloblastic anemia in PB and BM?
Hypersegmented neutrophils – 5 or more lobes
Macrocytic anemia with oval macrocytes
BM – Not needed for diagnosis
Nuclear to cytoplasmic dyssynchrony (megaloblastic change) in erythroids, granulocytes
What is the functional role of iron?
Where is iron stored?
Component of heme (80%)
Component of myoglobin, cytochromes, catalases (20%)
Liver, spleen, marrow
Hemosiderin: Breakdown of ferritin
What is the epidemiology for iron deficency?
Most common worldwide nutritional disorder
4-5 billion people worldwide
2 billion with IDA
Infants, children, and women are most susceptible
What are the clinical outcomes for iron deficient?
Iron Deficient Anemia (IDA)
Impaired cognition, work capacity
What are the causes for iron deficiency?
Dietary lack, i.e. milk-fed infants
Impaired absorption (duodenum)
Chronic blood loss
GI source (>50 y/o)
What transporter moves heme iron?
What transporter moves non-heme iron?
What is mucosal ferritin ?
Heme iron transporter
Reduced by duodenal cytochrome B – Vitamin C to ferrous iron (Fe2+)
Dication metal transporter – DMT-1
4500 molecules of iron per ferritin
What is the ferroportin transporter regulated by?
What kind of iron does it require?
Regulated by Hepcidin – Liver feedback of iron and inhibits Ferroportin 1
Must be ferrous
What oxidizes the iron?
What moves iron to the cells?
How can iron be lost?
Hephaestin oxidizes to 3+
Binds transferrin to moves it to cells
Iron can be lost via shedding of the GI epithelial cells
What is the serum ferritin study?
What is the difficulty with using ferritin?
Most sensitive assay for iron deficiency anemia
Ferritin has a high sensitivity and specificity for IDA when a cut-off equal to 30 microg/L is used
<12 is diagnostic of IDA
Ferritin is an acute phase reactant (increases during inflammation) making its usage during a chronic inflammatory process more cloudy
What is the use of serum iron study?
Not sensitive or specific
Many metabolic variations affect level
What is the total iron binding capacity study?
Essentially equivalent to a transferrin concentration
Normally 30% of transferrin is saturated with iron
Qualitatively opposite of serum ferritin levels