Iron Metabolism & The Anemic Patient
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What two forms of iron can be easily absorbed by the GI tract? What form is most iron in?
- Must be in ferrous (Fe2+) form or attached to heme
- Most is in ferric (Fe3+) form
Iron stores are regulated by ___________.
What is the obligate iron loss for men and nonmenstruating women? For menstruating women? How is most iron lost?
- ~1 mg/day
- ~2 mg/day
- Through shedding of cells from the GI tract
What are the two mechanisms that regulate iron absorption from the GI tract? Which mechanism is the normal regulator?
- Stores Regulator & Erythropoiesis Regulator
- Stores Regulator
How does the stores regulator work?
Controls iron absorption -- if stores are low it increases absorption, if stores are abundant it decreases absorption
How does the erythropoiesis regulator work?
- It is driven by bone marrow erythropoiesis --> any state of increased erythropoiesis increases iron absorption
- This mechanism is very powerful and can override the stores regulator -- this can cause iron overload in people with chronically increased erythropoiesis
What is the iron transport molecule in blood? How many molecules of iron can it carry, and in what form?
What is the cell surface receptor required for iron uptake known as? Where is the highest concentration of these receptors found? What are the two receptors called?
- Transferrin Receptors (TfR)
- Highest concentration is on erythroid precursors in the bone marrow, which have the highest requirement for iron (to make heme for hemoglobin)
- TfR1 & TfR2
What is the primary iron storage molecule? It is present in macrophages in the hepatocytes and the reticuloendothelial system (RES) in the bone marrow, liver, and spleen (a small amount is also present in the blood.
What is another form of iron in tissues; it may represent (at least in part) a degraded form of the above molecule. Iron in this form is not readily available for use.
If a person is not sick, what level in blood is directly proportional to body iron stores?
What is the primary regulator of iron metabolism? This decreases iron absorption from the GI tract and blocks iron release from macrophages; the result is to decrease iron in the plasma. It also blocks iron transfer to RBC precursors in the marrow; in cases of overexpression, what does this result in?
Where does iron absorption predominantly occur?
What is the normal amount of iron absorbed per day? What is the maximum that can be absorbed?
Most iron from the diet is in the Ferric form; however, it must be converted to the Ferrous form in order to be absorbed by GI enterocytes. What is required for this conversion to take place?
An acidic pH, derived from gastric acid
Release of iron from the GI enterocyte into the plasma is mediated by _________, which is the universal iron export mechanism from cells. What inhibits this process?
The synthesis of key iron-related molecules is controlled by the intracellular concentration of iron. What does intracellular iron bind to? What do these molecules then bind to on mRNA?
- Iron Regulatory Proteins (IRPs)
- Iron Responsive Elements (IREs)
5' iron _________ translation.
3' iron _________ translation.
Most of the iron in the body is circulating in RBCs in what form?
What is the total Body Iron Store in a 70 kg male? 60 kg female?
- Male -- 4.05 grams
- Female -- 2.34 grams
Most of the iron being transported by transferrin in blood is derived from the normal breakdown of senescent RBCs by macrophages of the RES. Each day about ____ - _____ milligrams of iron is recycled from the breakdown of RBCs (normally). Where does most of this iron go?
- Immediately transported back to the bone marrow to be put into new RBCs
Hepcidin is produced by what gene, located in the liver? It is synthesized in response to __________ __________ and ______ ________.
- Inflammatory Cytokines
- Iron Excess
How does Hepcidin block iron export from cells?
By binding to and degrading ferroportin, which is the iron export molecule from cells
What three proteins are involved in Hepcidin synthesis? What does a deficiency in these proteins result in?
- HFE, Hemojuvelin, & Transferrin Receptor 2 (TfR 2)
- Hemochromatosis due to deficient hepcidin synthesis
What Hepcidin synthesizing protein is produced by the gene most commonly mutated in hereditary hemochromatosis?
What are the four markers of Iron Status?
- Serum Iron Level
- Transferrin Level
- Transferrin Saturation %
- Serum Ferritin
What is the main cause of the symptoms seen in anemia (fatigue, SOB on exertion, palpitations)?
The inability to supply oxygen to tissues
What are some of the physical exam findings in anemia?
- Systolic Heart Murmur
- Unusual Physical Signs: Jaundice, Glossitis, & Angular Cheilitis
There are two different ways to approach an anemic patient. One is the ___________ approach, which depends largely on the reticulocyte count; the other is the _________ approach, which starts with evaluations of the MCV.
In this pathophysiologic subset of anemia classification, the marrow is not making red cells, but the cells produced look relatively normal. This is often because the marrow is either not being stimulated or something is suppressing the marrow.
In this pathophysiologic subset of anemia classification, the marrow is putting out plenty of red cells, but they are being lost (hemorrhage) or destroyed prematurely (hemolysis).
In this pathophysiologic subset of anemia classification, red cells are not able to mature normally in the marrow, and are thus not released into the blood. The RBCs that are produced may appear abnormal (abnormal size or shape). These may be cytoplasmic, nuclear, or combined defects.
This pathophysiologic subset of anemia classification refers to a state where the red cell mass is normal but the plasma volume is expanded. Since the measured Hgb is a ratio of red cell mass to total blood volume (RBCs + plasma), expansion of the plasma volume results in a decrease in the measured ratio even though the circulating red cell mass is normal. Thus, the patient is not truly anemic, even though the measured Hgb is low. When can this occur?
- Dilutional Anemia
- Pregnancy, Congestive Heart Failure, Splenomegaly
The first key question when approaching anemia from the pathophysiologic approach is "is the marrow working?" How do you tell whether the marrow is working?
Reticulocytes show up on a blood smear as RBCs which are slightly larger than mature RBCs, may lack the normal central pallor and have a slight blue color to the cytoplasm. What is this called?
Polychromasia or Polychromatophilia
Which pathophysiogic classification has a low reticulocyte count and normal RBC morphology?
Which pathophysiologic classification has an elevated reticulocyte count and RBCs that may be normal or abnormal depending on cause?
Which pathophysiologic classification has a low reticulocyte count and abnormal RBCs?
If the marrow is responding, should reticulocyte count be high or low in anemia? What does a "normal" reticulocyte count in someone who is anemic indicate?
- That the marrow is not mounting an effective response to the anemia
Hypoproliferative anemias occur if there is a decreased erythropoietin production, or decreased RBC precursors in the marrow. What are some common causes of these two factors?
- In decreased erythropoietin production, the marrow is not being told to make RBC's. Common causes include chronic renal insufficiency, anemia of chronic disease, and endocrine diseases.
- Common causes of decreased RBCs in the marrow are aplastic anemia and pure red cell aplasia
Maturation defect anemias occur when RBC precursors in the marrow are unable to mature and develop normally. What are the three divisions of these defects?
- Cytoplasmic: RBC precursors are unable to make Hgb
- Nuclear: RBC precursors are unable to mature the nucleas normally; however, they are able to make Hgb normally
- Combined: both cytoplasmic & nuclear defects occur
Cytoplasmic Maturation Defects involve defects in hemoglobin synthesis. What is the effect of these on MCV and RBC appearance? What are two common examples of these?
- Decreased MCV
- Hypochromic Anemias (Iron Deficiency) and Thalassemia
Nuclear Maturation Defects involve defects in nucleic acid synthesis. What is the effect of these on MCV? What are two common examples of these?
- Increased MCV
- Megaloblastic Anemia (Vit B12 or folate deficiency) & Chemotherapy (both interfere with DNA synthesis)
Combined Maturation Defects occur when there are abnormalities in both nuclear and cytoplasmic maturation. What is the most common effect on MCV? What is an example of this defect?
- Increased MCV
What are the two types of Hyperproliferative Anemias? the blood smear for these will tend to have __________, and the MCV is often a little _________.
- Hemorrhagic & Hemolytic
The microcytic anemias are usually due to a defective ___________ maturation. They are disorders of iron metabolism, globin synthesis, porphyrin & heme synthesis, and severe red cell fragmentation. What is the effect of these on MCV? What are three common examples of these?
- Usually normal MCV; may be decreased in severe, long-standing cases
- Iron Deficiency, Thalassemias, & Sideroblastic Anemias
Macrocytic anemias are usually either due to an increased ___________ count or _____________ maturation defects.
Microcytic anemias are generally ______chormic anemias
This type of anemia is caused by an inability to make the porphyrin part of the heme ring. There are a variety of different types of this anemia; it can be inherited or acquired -- usually due to ethanol or isoniazid. This type of anemia is not very common.
Normocytic anemias are those with a normal MCV. They can be divided into two groups: those with an appropriate marrow response, which have a __________ reticulocyte count; and those with an impaired marrow response, which have a ___________ reticulocyte count.
- Inappropriately Low
What are two common causes of a normocytic anemia with an appropriate marrow response?
- Acute Hemorrhage
- Hemolytic Anemias
What are three common causes of a normocytic anemia with an impaired marrow response?
- Marrow Hypoplasia: aplastic anemia or pure red cell aplasia
- Marrow Infiltration: primary myelofibrosis or blasts in acute leukemia
- Decreased Erythropoietin Production: kidney disease, liver disease, endocrine disorders, malnutrition, anemia or chronic inflammation
What are some common causes of macrocytic anemias?
- Megaloblastic Anemia
- Aplastic Anemia
- Chemotherapy, anti-retroviral drugs
What are the 6 most important questions to ask in a history of a patient presenting with anemia?
- Is the patient truly anemic?
- Is there evidence of blood loss?
- Is the anemia inherited or aquired?
- Is there evidence for hemolysis?
- Has the patient been exposed to medication or toxins that can cause anemia?
- Is there a systemic illness or non-hematologic organ dysfunction?
What are three common symptoms that would point toward hemolysis?
- Jaundice: bilirubin is a breakdown product of the heme ring. The bilirubin (mostly unconjugated) increases in hemolysis due to increased hemoglobin turnover, resulting in this
- Dark Urine: can occur due to hemoglobinuria, if the hemolysis is intravascular
- Abdominal Discomfort: due to splenomegaly
When evaluating a patient for anemia, abnormalities in a WBC count or the presence of abnormal or immature WBCs would suggest what?
An intrinsic hematologic abnormality: possibly leukemia, myelofibrosis, aplastic anemia, myelodysplasia
When evaluating a patient for anemia, what would a low platelet count reveal?
- A cause for bleeding
- Could indicate the presence of a serious intrinsic hematologic disease (leukemia, myelodysplasia, etc) rather than a pure red cell problem
Identify the peripheral smear phenomenon seen below. What does this often present in?
- Vitamin B12 Deficiency
Identify the peripheral smear phenomenon seen in the picture below. What is this often seen in?
- Hypersegmented Neutrophil
- Megaloblastic Anemia (Vitamin B12 or Folate Deficiency)
Identify the peripheral smear phenomenon seen below. What is this often seen in?
- Teardrop Cells
- Bone Marrow Fibrosis
Identify the peripheral smear phenomenon seen below. What is this often seen in?
- Sickle Cells
- Sickle Cell Anemia
What type of MCV (high or low) would indicate the need for an iron study?
What type of MCV (high or low) would indicate the need for a Vitamin B12, folate test?
If it is thought that a patient is hemolyzing, it is prudent to check for immune hemolytic anemia. What test is used for this?
Direct Antiglobulin (Coombs') Test: tests for antibodies on RBC surface; diagnosis of immune hemolytic anemia
What are some indications for a bone marrow biopsy or exam?
- Circulating Blasts
- Monoclonal Gammopathies
- Suspicion of Sideroblastic Anemia
- Moderate to Severe Anemia of Unknown Cause
- Combined Nutritional Deficiencies
Identify the slide below:
- Normal Bone Marrow Biopsy
- Mixture of hematopoietic cells and fat
What is this biopsy indicative of?
Aplastic Anemia: hypocellular bone marrow -- nearly all fat
What is this biopsy indicative of?
Myelofibrosis: replacement of bone marrow with fibrous tissue
What does the blue color in the image below indicate?
Blue color indicates presence of iron -- this would be a normal amount of iron for an adult
What is shown in the slide below? What is it indicative of?
- Ringed Sideroblasts --> nucleated RBC precursors that have rings of iron granules around the nucleus. The iron is located in the mitochrondira
- Sideroblastic Anemia
What molecule binds to free hemoglobin in the plasma? The complex is phagocytytized and consumed in the liver, and the level of this molecule in the blood drops. A decrease in this molecule is therefore a marker of what?
This is a test for previous or chronic intravascular hemolysis. If there is enough free hemoglobin in the blood that some is filtered through the glomerulus, the renal tubular cells will phagocytize the hemoglobin, and release and store the iron in the cytoplasm as this molecule. They are unable to transfer the iron back into the circulation, so it stays in the cytoplasm until the renal tubular cell is shed.
How are hemoglobinopathies such as Sickle Cell Disease diagnosed, as well as some types of Thalassemias?
How is Multiple Myeloma diagnosed?
A serum protein electrophoresis
This term means a space-occupying lesion in bone marrow. It could include metastatic carcinoma or other malignancies, fibrosis (called myelofibrosis in the bone marrow), granulomas, or even bone (osteosclerosis).
What are the four common causes of Hypoproliferative Anemias?
- Marrow Aplasia
- Chronic Disease/Inflammation
- Organ Failure
What is the most common cause of iron deficiency?
Gastrointestinal Blood Loss: can be due to GI malignancy, peptic ulcer disease, gastritis, inflammatory bowel disease, etc.
What type of anemia is likely indicated below? The arrow is pointing to a normal lymphocyte, which normal red cells should be similar in size to.
- Iron Deficiency Anemia
- Cells are microcytic and hypochromic
A patient with iron deficiency has ________ serum iron, _______ transferrin levels (TIBC), ________ saturation levels, and ________ ferritin levels.
- Very Decreased
A patient with a chronic disease has ________ serum iron, _______ transferrin levels (TIBC), ________ saturation levels, and ________ ferritin levels.
A patient with a combined iron deficiency and chronic disease will have ________ serum iron, _______ transferrin levels (TIBC), ________ saturation levels, and ________ ferritin levels.
What is the most common cause of anemia in sick or hospitalized patients?
Anemia of Chronic Disease (Chronic Inflammation)
An increase in _________ __________ is the key to anemia of chronic disease. These can have multiple effects, including suppression of erythropoietin production by the kidney, suppression of marrow response to erythropoietin, stimulation of production of hepcidin, and stimulation of macrophages which then increase RBC phagocytosis.
In Anemia of Chronic Disease, there is a mild to moderate ________ in hemoglobin, MCV is usually ________, reticulocyte count is ___________, and RBCs are usually _________ and __________ on smear.
- Not appropriately increased for anemia
- Normocytic & Normochromic
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