Chapter 3 Essential Hematology (Hypochromic Anemias) Flashcards
Iron deficiency is the most common and important cause of which type of anemia?
Microcytic hypochromic anemia
Which 2 lab values are reduced in microcytic hypochromic anemias?
- MCV: mean corpuscular volume
2. MCH: mean corpuscular hemoglobin
What are the 2 major differential diagnoses in microcytic hypochromic anemias?
- Thalassemia
2. Anemia of chronic disease
What are the 4 possible causes of microcytic hypochromic anemia?
- Lack of iron (iron deficiency)
- Lack of iron release from macrophages to serum (anemia of chronic inflm/disease)
- Failure of protoporphyrin synthesis (sideroblastic anemia)
- Failure of globin synthesis (thalassemia)
Lead inhibits the synthesis of what?
Heme and globin
How many atoms of iron can transferrin hold?
Up to 2
T or F. Transferrin is recycled.
T
What happens to RBCs at the end of their life and the iron they contained?
Broken down by macrophages and the iron is released from hemoglobin. The iron then enters the plasma and provides most of the iron bound to transferrin.
How is iron stored in macrophages?
Ferritin and hemosiderin
Is ferritin water soluble?
Yes
What is apoferritin?
The outer protein shell of ferritin that consists of 22 subunits and an iron-phosphate-hydroxide core.
Is apoferritin visible by light microscopy?
No
How many atoms of iron can one molecule of apoferritin bind?
4,000-5,000
Most of the iron in the body is contained in what?
In circulating hemoglobin. It is reutilized for hemoglobin synthesis after the red cells die.
Iron in macrophages is transferred to plasma transferrin and then transferred to what?
Bone marrow erythroblasts
T or F. Iron absorbed from the diet is normally just sufficient to make up for iron loss.
T: about 1 mg is absorbed to balance the 1 mg lost in urine, feces, nails, hair, and skin.
Is hemosiderin water soluble?
No: it is an insoluble protein-iron complex.
What is hemosiderin derived from?
Partial lysosomal digestion of aggregates of ferritin molecules.
What stain must be used to see hemosiderin on light microscopy?
Prussian blue
What form is iron in when in ferritin and hemosiderin?
Ferric form (Fe3+)
Describe the process of iron mobilization when bound to ferritin and hemosiderin.
Bound in ferric form. Reduced to ferrous form for mobilization (vitamin C required).
What copper-containing enzyme catalyzes the oxidation of iron to the ferric form for binding to plasma transferrin?
Ceruloplasmin
Where else is iron found in the body?
In muscle as myoglobin and also in most cells in iron-containing enzymes (cytochromes, succinic dehydrogenase, catalase, etc.).
T or F. Iron in tissue is less likely to become depleted than the iron in hemosiderin, ferritin, and hemoglobin in states of iron deficiency.
T: but some reduction of heme-containing enzymes may occur.
What is the average amount of iron in hemoglobin in an adult?
Male: 2.4 g
Female: 1.7 g
What is the average amount of iron in ferritin and hemosiderin in an adult?
Male: 0.3-1.5 g
Female: 0-1.0 g
What 4 molecules are linked to iron status?
- Ferritin
- TfR1 (transferrin receptor 1)
- ALA-S (aminolevulinic acid synthase)
- DMT-1 (divalent metal transporter 1)
Iron overload causes what?
High ferritin. Low TfR1 and DMT-1.
Iron deficiency causes what?
Low ferritin and ALA-S. High TfR1.
What causes the rise and fall of those 4 molecules in response to iron levels?
Binding of IRP (iron regulatory protein) to IREs (iron response elements) on the ferritin, TfR1, ALA-S, and DMT-1 mRNA molecules.
In regards to IRPs and IREs, what does iron deficiency cause? Iron overload?
Iron deficiency increases the ability of IRP to bind to IREs, whereas iron overload reduces the binding.
In regards to the binding of IRP to IREs, binding upstream (5’) of the coding gene does what? Downstream (3’) binding?
Upstream: reduces translation.
Downstream: stabilizes the mRNA thus increasing translation.
What does IRP sense to regulate expression of TfR1, DMT-1, and ferritin?
Senses intracellular iron levels.
IREs have what structure?
Stem-loop structures.
IRP binding to the IRE within the 3’ UTR of TfR1 and DMT-1 mRNA leads to what?
Stabilization of the mRNA and thus increased protein synthesis.
IRP binding to the IRE within the 5’ UTR of ferritin and ALA-S mRNA leads to what?
Reduced translation.
When iron levels are high, IRP does what?
Binds iron and has a reduced affinity for the IREs.
When iron levels are low, IRP does what?
Readily binds to IREs.
T or F. When plasma iron levels are high and transferrin is saturated, the amount of iron transferred to parenchymal cells is increased.
T. Parenchymal cells of liver, endocrine organs, pancreas, and heart.
What organ synthesizes hepcidin?
Liver
T or F. Hepcidin is the major hormonal regulator or iron homeostasis.
T
What does hepcidin do?
Inhibits iron release from macrophages and intestinal epithelial cells by accelerating the degradation of ferroportin mRNA. Note: ferroportin is a transmembrane iron exporter.
What 6 molecules stimulate hepcidin synthesis?
- BMP (bone morphogenetic protein)
- Ferroportin
- HJV (hemojuvelin)
- IL-6
- Transferrin
- Transcription factor Smad4
T or F. Membrane bound HJV is a co-receptor with BMP which stimulates hepcidin expression.
T
What does matriptase 2 do?
Digests membrane bound HJV. In iron deficiency, matriptase 2 activity is increased resulting in decreased hepcidin synthesis.
What 2 proteins do erythroblasts secrete to suppress hepcidin secretion?
- GDF15
2. TWSG1
T or F. Hypoxia suppresses hepcidin synthesis whereas in inflammation, IL-6 and other cytokines increase hepcidin synthesis.
T
What is the best source for dietary iron?
Meat: in particular liver.
DMT-1 is involved in the transfer of dietary iron from where to where?
From the lumen of the gut across the enterocyte microvilli.
What protein at the basolateral surface of enterocytes controls the exit of iron from the cell into plasma?
Ferroportin
T or F. The amount of iron absorbed is regulated according to the body’s needs by changing levels of DMT-1 and ferroportin.
T
What enzyme converts Fe3+ to Fe2+ at the apical surface of enterocytes?
Ferrireductase
What copper-containing enzyme converts Fe2+ to Fe3+ at the basolateral surface of entertocytes?
Ferrioxidase
T or F. Pregnant, adolescent, and menstruating females require the most amount of iron.
T
In the development of iron deficiency, what must be completely depleted before anemia occurs?
The reticuloendothelial stores (hemosiderin and ferritin).
In addition to the general signs and symptoms of anemia, what other things can be observed in the patient?
Painless glossitis, angular stomatitis, koilonychia (brittle, ridged, or spoon nails), dysphagia as a result of pharyngeal webs, and picca.
What 3 signs are seen in iron deficient children?
- Irritability
- Poor cognitive function
- Decline in psychomotor development
In developed countries, what is the major cause of iron deficiency?
Chronic blood loss especially uterine or GI tract.
How many mg of iron is contained within a liter of whole blood?
500 mg
What patient populations are at higher risk for iron deficiency anemia?
Infants, adolescents, pregnant women, lactating women, and menstruating women.
Newborn infants have a store of iron derived from what?
Delayed clamping of the cord and the breakdown of excess red cells.
T or F. From 3-6 months of age, there is a tendency for negative iron balance because of growth.
T
From 6 months on, how is iron deficiency prevented in infants?
Supplemented formula milk and mixed feeding particularly with iron-fortified foods.
What are 3 reasons pregnancy requires more iron?
- Increased maternal red cell mass
- Transfer of 300 mg of iron to the fetus
- Blood loss at delivery
When is iron therapy required for pregnant women?
If Hgb falls below 10 g/dL or the MCV is below 82 fL in the third trimester.
T or F. Hookworm may aggravate iron deficiency.
T
What do target cells look like and what are they a result of?
Target cells look like bullseyes: red cells with white center with the membrane forming a red ring around it. Result of decrease in hemoglobin content.
Dimorphic red cell populations (macrocytic and hypochromic/microcytic) on PBS are seen when?
When iron deficiency is associated with severe folate or vitamin B12 deficiency. Or in patients with iron def anemia who have just received recent iron therapy.
What stain is used to assess bone marrow iron?
Prussian blue
In iron deficiency anemia, the serum iron does what? TIBC?
Serum iron decreases. TIBC increases.
In anemias of chronic disease, the serum iron does what? TIBC?
Both decrease.
Normal serum contains how many g/L of transferrin?
2-4 g/L
T or F. 1 g/L transferrin = 20 umol/L binding capacity
T
What is the normal range for serum iron?
10-30 umol/L
What is the normal range for TIBC?
40-75 umol/L
What is the normal range for serum ferritin?
Male: 40-340 ug/L
Female: 14-150 ug/L
Serum ferritin values are directly proportional to what?
Amount of iron in the storage pool.
In iron def anemia, is serum ferritin high or low?
Very low.
What does a raised serum ferritin indicate (can mean 3 things)?
- Iron overload
- Excess release of ferritin from damaged tissues
- Acute phase response (inflammation)
What happens to the serum ferritin levels in anemia of chronic disease?
Normal or raised.
How would you confirm a diagnosis of iron def anemia?
Hypochromic microcytic anemia seen on PBS. To confirm, you would find low serum iron, low serum ferritin, and a raised TIBC.
What are the 2 most common causes of iron def anemia in premenopausal women?
- Menorrhagia
- Repeated pregnancies
If neither of these, usually a clotting or platelet abnormality.
What is the main cause of iron def anemia in men and postmenopausal women?
GI bleed. If not, think hematuria or hemosiderinuria.
What are the 2 steps in treating iron def anemia?
- Fix the underlying cause
2. Give iron to correct anemia and replenish iron stores
What is the best preparation of oral iron to give?
Ferrous sulphate: cheap, 67mg in each 200mg tablet. Best given on empty stomach q6h. Side effects can be reduced by giving with food.
T or F. Iron fortification of the diet in infants in Africa reduces the incidence of anemia but increases susceptibility to malaria.
T
If non-responsive to oral iron therapy, what should be given?
Parenteral iron
What is IRIDA (iron refractory iron def anemia)?
Rare autosomal recessive cases of hypochromic microcytic anemia caused by inherited mutations of matriptase 2 or DMT-1 genes.
What are the 5 characteristics of anemia of chronic disease?
- Normochromic, normocytic, or mildly hypochromic anemia
- Mild and non-progressive anemia (Hgb rarely < 9 g/dL)
- Low serum iron and TIBC
- Normal or high serum ferritin
- Normal bone marrow storage iron but reduced erythroblast iron
What are some examples of infections that can cause anemia of chronic disease?
Pulmonary abscess, TB, osteomyelitis, pneumonia, bacterial endocarditis.
What are some examples of non-infectious diseases that can cause anemia of chronic disease?
RA, SLE & other connective tissue diseases, sarcoidosis, Crohn’s, Gaucher’s.
What are some examples of malignant disease that can cause anemia of chronic disease?
Carcinoma, lymphoma, sarcoma.
The pathogenesis of anemia of chronic disease?
Decreased release of iron from macrophages to plasma because of raised serum hepcidin levels, reduced red cell lifespan, and an inadequate EPO response (caused by the effects of cytokines such as IL-1 and TNF on erythropoiesis).
What is the treatment for anemia of chronic disease?
Treating the underlying cause. This anemia does not respond to iron therapy. EPO injections sometimes help.
Sideroblastic anemia is characterized by the presence of what in the bone marrow?
Presence of many ring sideroblasts.
What are sideroblasts?
Abnormal erythroblasts that contain numerous iron granules arranged in a ring or collar around the nucleus.
What percentage of sideroblasts must be present in the BM to diagnose sideroblastic anemia?
15%
A defect in what molecule synthesis causes sideroblastic anemia?
Heme synthesis
In hereditary forms of sideroblastic anemia, PBS shows what type of red cells?
Markedly hypochromic and microcytic.
The most common mutation causing hereditary sideroblastic anemia is in what gene?
ALA-S gene on the X chromosome.
What coenzyme does ALA-S require?
Vitamin B6 (pyridoxal-6-phosphate).
Patients with hereditary sideroblastic anemia show response with what therapy?
Pyridoxine therapy.
In severe cases of sideroblastic anemia what complications are seen with repeated blood transfusions?
Transfusional iron overload requiring iron chelation therapy.
Refractory anemia with ring sideroblasts is seen in patients with what syndrome?
Myelodysplasia
Lead inhibits the synthesis of what 2 molecules?
Heme and globin
How does lead poisoning cause an accumulation of RNA in denatured red cells?
Lead inhibits the enzyme pyrimidine 5’ nucleotidase which normally breaks down RNA. The RNA in the red cells gives the appearance called basophilic stippling with Romanowsky stain.
T or F. Lead poisoning leads to an anemia that may be hypochromic or hemolytic, and the bone marrow may show ring sideroblasts.
T
T or F. Free erythrocyte protoporphyrin is elevated in lead poisoning anemia.
T
In hypochromic anemias, why is the clinical history important?
It may reveal the source of a hemorrhage or the presence of a chronic disease.
In hypochromic anemias, what might the country of origin and family history suggest?
Possible diagnosis of thalassemia or other genetic defect of hemoglobin.
In hypochromic anemias, why is the physical exam important?
It may help determine the site of hemorrhage, reveal features of a chronic inflammatory or malignant disease, koilonychia. Or in some hemoglobinopathies, it may reveal an enlarged spleen or bony deformities.
In thalassemia trait, what is the size of the red cells? The MCV? Red cell count?
The red cells are small and the MCV is 70fL or less even when anemia is mild or absent. Red cell count is elevated (>5.5x10^12/L).
In iron deficiency anemia, how do the lab values correspond to the severity?
Lab values fall progressively as severity worsens. When mild, values are normal or slightly low.
In anemia of chronic disorder, are the lab values significantly low? MCV?
Lab values are only slightly low. MCV ranges between 75-82 fL.
What is measured to confirm a diagnosis of iron deficiency anemia?
Serum iron and TIBC. Or serum ferritin.
What test is performed to confirm diagnosis of thalassemia or hemoglobin genetic defect?
Hgb electrophoresis will show Hgb A2 and/or Hgb F. This only confirms beta thalassemia.
T or F. Beta thalassemia is confirmed by elevated Hgb A2 over 3.5%.
T
How is alpha thalassemia diagnosed?
Diagnosis made by exclusion of all other causes of hypochromic red cells and by a red cell count >5.5x10^12/L. In some pt’s, occasional red cells show deposits of Hgb H in reticulocyte preparations.
How do you confirm a diagnosis of sideroblastic anemia?
Bone marrow biopsy shows presence of sideroblasts. Note: BM Bx’s are usually not needed to diagnose any of the other hypochromic anemias.
