1. Hematology 425 Disorders of Iron Metabolism
Russ Morrison
October 25, 2006
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2. Anemia, General Concepts
Anemia is the result of one of three causes
RBC production is impaired
RBC life span is shortened
Loss of RBCs (ie: bleeding)
Anemias associated with iron belong to the second category, impaired production
RBC production requires three primary constituents
Heme
Globin
iron
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3. Anemia, General Concepts
Lack of available iron results in
Iron deficiency anemia (IDA) OR
Anemia of chronic disease (ACD)
Inadequate availability of heme results in an excess of iron manifested in sideroblastic anemias, discussed here
Inadequate globin production results in the thalassemias, covered in Chapter 25
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4. Utilization of Iron
Iron is absorbed from the diet in the small intestine
Iron is carried by transferrin to cells in need of iron
Iron is incorporated into the cell where it is held as ferritin until being incorporated into its final functional molecule
The functional molecule may be a heme-based cytochrome, muscle myoglobin or in the case of developing RBCs, hemoglobin
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5. Utilization of Iron Iron may be unavailable due to one of 2 causes
Inadequate stores of body iron
Impaired mobilization of the iron to the cells
Anemia associated with inadequate stores is iron deficiency anemia
Anemia resulting from impaired mobilization is anemia of chronic disease and is linked to chronic inflammatory diseases such as arthritis
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6. Utilization of Iron
Sometimes the iron supply is adequate and mobilization is unimpaired, but an intrinsic red blood cell defect prevents incorporation of iron into heme
When this happens, the resulting anemia is termed sideroblastic, referring to the presence of iron in the developing red blood cells, particularly the erythroblast using a prussian blue stain
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7. Iron Deficiency Anemia (IDA)
IDA develops
When the intake of iron is inadequate to meet demand
When the need for iron expands faster than the supply
When there is chronic loss of hemoglobin from the body (bleeding)
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8. Iron Deficiency Anemia (IDA)
Inadequate intake
IDA develops as the erythron is slowly starved for iron
Each day approximately 1 mg of iron is lost
Replacing 1 mg of iron in the diet daily will maintain iron balance
When dietary intake is inadequate, the body’s stores will be depleted over time
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9. Iron Deficiency Anemia (IDA)
Inadequate intake
Red cell production eventually slows due the the inability to provide the iron necessary to produce hemoglobin
The anemia will become apparent when the RBC production rate cannot replace the 1% of RBCs lost naturally each day
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10. Iron Deficiency Anemia (IDA)
Increased Need
IDA can also develop when the level of iron intake becomes inadequate to meet the needs of an expanding erythron
This type of anemia is seen during phases of rapid growth, infancy, childhood, adolescence, pregnancy, nursing mothers
What has been an adequate intake of iron becomes inadequate during these times of additional need
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11. Iron Deficiency Anemia (IDA)
Chronic Loss
The third way that IDA develops is with excessive loss of hemoglobin through bleeding or hemolysis
Any condition which produces a slow, low-level loss of RBCs may result in IDA
In women, heavy menstrual bleeding or bleeding associated with fibroid tumors can lead to IDA
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12. Iron Deficiency Anemia (IDA)
Chronic Loss
GI bleeding from ulcers or tumors can also be the chronic loss that leads to IDA
Kidney stones or tumors can lead to IDA through blood loss via the urine
Chronic intravascular hemolytic processes, such as PNH can also lead to IDA
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13. Iron Deficiency Anemia (IDA)
Pathogenesis of IDA
IDA is a slowly developing process that passes through distinct stages as depicted in fig.17-1
Iron is distributed in three compartments
Storage compartment, principally as ferritin in the BM macrophages and liver cells
Transport compartment of serum transferrin
Functional compartment of hemoglobin, myoglobin and cytochromes
Hgb and intracellular ferritin make up 95% of the total iron distribution
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14. Stages of Iron Deficiency Anemia
As the intake of iron fails to keep up with demand, a negative iron balance continues and stages of iron depletion develop
Stage 1
Progressive loss of storage iron
The body’s reserve of iron maintains both the transport and functional compartments so RBC development during Stage 1 is normal
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15. Stages of Iron Deficiency Anemia
During this stage there is no evidence of anemia in the PB and the patient has no symptoms
Typical IDA laboratory tests would be normal
Ferritin levels would be low, indicating decreased storage iron, however, there would be no indication to perform this test
50% of US infants are in Stage 1 iron deficiency at any given time
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16. Stages of Iron Deficiency Anemia
In stage 2 the storage pool of iron is exhausted
RBC production can remain normal as long as the transport compartment holds up
Clinical anemia is still not evident, though the individual’s Hgb may begin to drop
Ferritin levels and serum iron will be low while TIBC (transferrin) levels will rise
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17. Stages of Iron Deficiency Anemia
Prussian blue staining of the BM would demonstrate no stored iron
Iron-deficient erythropoiesis would be evident
As in stage 1, stage 2 is sub-clinical and testing is not likely to occur
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18. Stages of Iron Deficiency Anemia
Stage 3 is characterized by clinical anemia
Hgb and Hct are low
RBCs are unable to develop normally as cell divisions per precursor increase in an attempt to meet demand for RBCs and O2
Smaller cells with adequate Hgb lead to microcytes with inadequate Hgb leading to the microcytic and hypochromic cells expected in IDA
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19. Stages of Iron Deficiency Anemia
Iron studies are abnormal, decreased serum iron and ferritin with increased TIBC
Patient will exhibit nonspecific symptoms of anemia
Fatigue and weakness, especially on exertion
Pallor
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20. Stages of Iron Deficiency Anemia
More severe signs (including glossitis, inflamed cracks at the corners of the mouth (angular chelosis) and koiloncychia) are rarely seen n the US.
There are many apparently healthy individuals who are iron deficient
Since no symptoms appear until late in stage 2 and routine laboratory tests do not point to the deficiency, most patients are diagnosed relatively late in the progression of the iron depletion
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21. Epidemiology of IDA
Some groups are more predisposed to IDA than others
Menstruating women, particularly adolescent girls who are also still growing
Pregnancy and nursing
Growing children should receive iron supplements after 6 months of age as fetal stores are depleted and milk (cow or breast) is not an adequate source of iron
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22. Epidemiology of IDA
Iron deficiency is rare in adult men and postmenopausal women because the body is so good at conserving the iron lost as RBCs die
GI ulcers, tumors or hemorrhoids may be suspected for iron deficient patients in these groups if dietary intake is adequate
Aspirin and alcohol can lead to chronic bleeding and IDA
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23. Epidemiology of IDA
Dietary deficiency may be seen in the elderly who do not eat well and lose gastric acidity which aids in the absorption of iron
Infestation by hookworms (Necator americanus and Ancylostoma duodenale) may lead to IDA
“marching anemia” may be seen in soldiers and long distance runners as RBCs are hemolyzed by constant foot pounding
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24. Laboratory Diagnosis of IDA
Laboratory tests maybe grouped into three general categories:
Screening
Diagnostic
specialized
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25. Laboratory Diagnosis of IDA
Screening
After iron-deficient erythropoiesis begins
PB will show microcytosis and hypochromia
Decreased Hgb
RDW > 15%
Values for MCV, MCH and MCHC progressively fall
RBC count and Hct decrease
Reticulocyte count confirms diminished RBC production
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26. Laboratory Diagnosis of IDA
Anisocytosis and poikilocytosis increases
Target cells may be present
Thrombocytosis may be present if the IDA is the result of a chronic bleed
IDA is suspected when the CBC shows a hypochromic, microcytic anemia with elevated RDW, but no additional consistent morphologic changes in the RBCs
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27. Diagnosis of Iron Deficiency
Iron studies are necessary to confirm IDA
Ferritin and serum iron will be decreased
Transferrin levels rise as the body tries to capture as much iron as possible
Iron studies should be drawn fasting in the early morning as iron demonstrates diurnal variation
Iron absorbed from a meal can falsely elevate serum iron levels
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28. Specialized Tests in IDA
Tests for accumulated porphyrin precursors to heme will be elevated
Free erythrocyte protoporphyrin (FEP) accumulates in the absence of iron and may be chelated with zinc to form zinc protoporphyrin (ZPP)
Serum transferrin receptors can be assayed and levels will rise as IDA progresses
BM is usually not indicated, but cells will show decreased iron and rubricytes will show cytoplasmic asynchrony and a “shaggy” appearance
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29. Treatment of IDA
First treat any underlying cause (hookworms, tumors, ulcers)
Supplement iron intake to replenish iron stores (ferrous sulfate, 3 tablets 3 times per day, 60 mg) for 6 months
Transfusion is rarely necessary and is not warranted as the risk is too great
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30. Response to Treatment in IDA
Rapid turnaround following treatment
Reticulocyte counts begin to rise within 5 to 10 days
Hgb will begin to rise within 2 to 3 weeks and should be “normal” within 2 months
PB smear will exhibit iron-deficient population of cells for several months, but the normal RBC population will gradually rise
Failure to respond to iron therapy indicates further investigation should be performed
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31. Anemia of Chronic Disease
Anemia of Chronic Disease (ACD) is the most common anemia among hospitalized patients
Anemia is commonly seen with systemic diseases including chronic inflammatory conditions like arthritis, chronic infections such as tuberculosis and malignancies
Though the underlying diseases are varied, the anemia may be from a single cause (ACD)
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32. Anemia of Chronic Disease
Chronic blood loss does not lead to ACD, but leads to IDA
ACD may be more correctly termed anemia of chronic inflammation
Full understanding of the mechanisms of ACD is not yet available
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33. ACD - Pathophysiology
ACD may be related to impaired ferrokinetics or to diminished erythropoiesis
It is known that:
Inflammatory cellular products impair the mobilization of iron from macrophages to developing RBCs
Inflammatory cellular products also impair the production and action of erythropoietin
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34. ACD - Pathophysiology
The main feature of ACD is sideropenia in the face of abundant iron stores
BM macrophages will demonstrate abundant stainable iron, while developing red blood cells will show inadequate iron stores
Cytokines (IL-1, beta and gamma interferon) appear to affect erythropoiesis by inhibition of both production and action of EPO.
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35. Laboratory Diagnosis of ACD
PB picture shows mild anemia (Hgb 9-11 g/dL) without reticulocytosis
Normocytic, normochromic RBCs
Inflammatory process may show increased WBCs and/or thrombocytosis
Iron studies show low serum iron and TIBC, Transferrin saturation may be normal or low and ferritin is usually increased
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36. Laboratory Diagnosis of ACD
Failure to incorporate iron into heme causes elevated FEP
BM demonstrates hypoproliferation of RBCs consistent with the lack of reticulocytes in the PB
Prussian blue staining of the BM confirms abundant storage iron in macrophages, but not in RBC precursors
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37. Laboratory Diagnosis of ACD
IDA and ACD can be distinguished by measuring serum transferrin receptors as the levels will rise during IDA but remain normal during ACD
Treatment with therapeutic EPO can correct ACD, however, the anemia is not severe and the cost is usually not warranted
The best course of treatment is control or removal of the underlying inflammatory condition
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38. Sideroblastic Anemias
Sideroblastic anemia is caused by conditions which interfere with production of adequate amounts of heme
Anemia may be hypochromic and microcytic, but iron is abundant in the marrow
Prussian blue stain will demonstrate normoblats with iron deposits in the mitochondria surrounding the nucleus
These ringed sideroblasts (fig.17-4) are characteristic of the sideroblastic anemias
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39. Sideroblastic Anemias
Incorporation of iron into heme can be blocked when any of the enzymes of the heme synthetic pathway (fig.17-5) are deficient or impaired
Deficiencies of these enzymes may be hereditary, as in the porphyrias, or acquired, as in drug toxicity (chloramphenicol or isoniazid) and heavy metal poisoning
The most common heavy metal poisoning is lead poisoning
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40. Sideroblastic Anemias
Iron studies in sideroblastic anemias will show elevated total iron, variable iron-binding capacity, normal transferrin saturation, and normal to increased ferritin
Accumulation of products of the heme synthetic pathway would be positive
Porphyrias are diseases characterized by impaired production of heme, usually referring to hereditary causes (table 17-2)
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41. Lead Poisoning
Lead poisoning interferes at several steps in heme synthesis which prevents incorporation of iron into heme
Lead also impairs G6PD creating a hemolytic component of this anemia
Children are vulnerable due to ingestion of paint chips and dust from paints used prior to 1970, which often contained lead
Lead poisoning in children can lead to irreversible brain damage
Treatment is removing the source of the lead or chelating drugs may be used to facilitate excretion in the urine
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42. Iron Overload
Iron overload occurs as a result of the lack of a mechanism for iron excretion
Iron overload (hemochromatosis) occurs when transfusions are used to sustain patients with chronic anemias (i.e. thalassemia) and is called transfusion-related hemochromatosis or hemosiderosis
A defective HFE gene (C6) can cause hereditary hemochromatosis
Men develop symptoms earlier in life because women are protected by blood loss of the menstrual cycle
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43. Iron Overload
Homozygotes with the defective HFE gene develop more sever symptoms than heterozygotes
Free iron becomes available when ferritin and hemosiderin are saturated
Free iron causes tissue damage by creating free radicals that cause cell membrane damage
Tissues susceptible to damage by excess iron include liver, pancreas, skin and heart muscle
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44. Iron Overload
Iron overload can be primary, as in hereditary hemochromatosis (HH), or secondary to chronic anemias and their treatments (transfusion)
In either case, the toxic effects of excess iron can lead to serious health problems
Elevated transferrin saturation is a good screening test for hemochromatosis
HH can be diagnosed using PCR to amplify and identify the mutated genes
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45. Iron Overload
HH is treated by lifelong, periodic phlebotomy to induce a mild iron deficiency anemia and keep body iron levels low
Transfusion-related acquired hemochromatosis must be treated with iron-chelating drugs such as desferrioxamine when the transfusions must continue
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