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Hematology 425 Hematology 425 Disorders of Iron MetabolismDisorders of Iron Metabolism

Russ MorrisonOctober 25, 2006

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Anemia, General ConceptsAnemia, General Concepts Anemia is the result of one of three

causes1. RBC production is impaired2. RBC life span is shortened3. Loss of RBCs (ie: bleeding) Anemias associated with iron belong to

the second category, impaired production RBC production requires three primary

constituents1. Heme2. Globin3. iron

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Anemia, General ConceptsAnemia, General Concepts Lack of available iron results in1. Iron deficiency anemia (IDA)OR2. 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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Utilization of IronUtilization of IronIron is absorbed from the diet in the small

intestineIron is carried by transferrin to cells in

need of ironIron 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

05/09/235

Utilization of IronUtilization of Iron Iron may be unavailable due to one of 2 causes1. Inadequate stores of body iron2. 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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Utilization of IronUtilization of IronSometimes 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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Iron Deficiency Anemia (IDA)Iron Deficiency Anemia (IDA) IDA develops 1. When the intake of iron is inadequate to

meet demand2. When the need for iron expands faster

than the supply3. When there is chronic loss of

hemoglobin from the body (bleeding)

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Iron Deficiency Anemia (IDA)Iron Deficiency Anemia (IDA)Inadequate intakeIDA develops as the erythron is slowly

starved for ironEach day approximately 1 mg of iron is

lostReplacing 1 mg of iron in the diet daily

will maintain iron balanceWhen dietary intake is inadequate, the

body’s stores will be depleted over time

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Iron Deficiency Anemia (IDA)Iron Deficiency Anemia (IDA)Inadequate intakeRed 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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Iron Deficiency Anemia (IDA)Iron Deficiency Anemia (IDA)Increased NeedIDA 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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Iron Deficiency Anemia (IDA)Iron Deficiency Anemia (IDA)Chronic LossThe 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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Iron Deficiency Anemia (IDA)Iron Deficiency Anemia (IDA)Chronic LossGI bleeding from ulcers or tumors can also

be the chronic loss that leads to IDAKidney stones or tumors can lead to IDA

through blood loss via the urineChronic intravascular hemolytic processes,

such as PNH can also lead to IDA

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Iron Deficiency Anemia (IDA)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 compartments1. Storage compartment, principally as ferritin in

the BM macrophages and liver cells2. Transport compartment of serum transferrin3. Functional compartment of hemoglobin,

myoglobin and cytochromes Hgb and intracellular ferritin make up 95% of

the total iron distribution

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Stages of Iron Deficiency AnemiaStages 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 1Progressive loss of storage ironThe body’s reserve of iron maintains both

the transport and functional compartments so RBC development during Stage 1 is normal

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Stages of Iron Deficiency AnemiaStages of Iron Deficiency Anemia

Stage 1 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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Stages of Iron Deficiency AnemiaStages of Iron Deficiency Anemia

Stage 2In stage 2 the storage pool of iron is

exhaustedRBC production can remain normal as long

as the transport compartment holds upClinical anemia is still not evident, though

the individual’s Hgb may begin to dropFerritin levels and serum iron will be low

while TIBC (transferrin) levels will rise

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Stages of Iron Deficiency AnemiaStages of Iron Deficiency Anemia

Stage 2Prussian blue staining of the BM would

demonstrate no stored ironIron-deficient erythropoiesis would be

evidentAs in stage 1, stage 2 is sub-clinical and

testing is not likely to occur

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Stages of Iron Deficiency AnemiaStages of Iron Deficiency Anemia

Stage 3Stage 3 is characterized by clinical anemiaHgb and Hct are lowRBCs 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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Stages of Iron Deficiency AnemiaStages of Iron Deficiency Anemia

Stage 3 Iron studies are abnormal, decreased

serum iron and ferritin with increased TIBC

Patient will exhibit nonspecific symptoms of anemia

1. Fatigue and weakness, especially on exertion

2. Pallor

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Stages of Iron Deficiency AnemiaStages of Iron Deficiency Anemia

Stage 3 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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Epidemiology of IDAEpidemiology of IDA Some groups are more predisposed to

IDA than others1. Menstruating women, particularly

adolescent girls who are also still growing

2. Pregnancy and nursing3. 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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Epidemiology of IDAEpidemiology of IDAIron 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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Epidemiology of IDAEpidemiology of IDADietary 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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Laboratory Diagnosis of IDALaboratory Diagnosis of IDA Laboratory tests maybe grouped into

three general categories:1. Screening2. Diagnostic3. specialized

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Laboratory Diagnosis of IDALaboratory Diagnosis of IDA Screening After iron-deficient erythropoiesis begins1. PB will show microcytosis and hypochromia2. Decreased Hgb3. RDW > 15%4. Values for MCV, MCH and MCHC

progressively fall5. RBC count and Hct decrease6. Reticulocyte count confirms diminished RBC

production

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Laboratory Diagnosis of IDALaboratory Diagnosis of IDAAnisocytosis and poikilocytosis increasesTarget cells may be presentThrombocytosis may be present if the IDA

is the result of a chronic bleedIDA 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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Diagnosis of Iron DeficiencyDiagnosis of Iron DeficiencyIron studies are necessary to confirm IDAFerritin and serum iron will be decreasedTransferrin levels rise as the body tries to

capture as much iron as possibleIron 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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Specialized Tests in IDASpecialized 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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Treatment of IDATreatment of IDAFirst 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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Response to Treatment in IDAResponse 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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Anemia of Chronic DiseaseAnemia of Chronic DiseaseAnemia 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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Anemia of Chronic DiseaseAnemia of Chronic DiseaseChronic blood loss does not lead to ACD,

but leads to IDAACD may be more correctly termed

anemia of chronic inflammationFull understanding of the mechanisms of

ACD is not yet available

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ACD - PathophysiologyACD - Pathophysiology ACD may be related to impaired ferrokinetics

or to diminished erythropoiesis It is known that:1. Inflammatory cellular products impair the

mobilization of iron from macrophages to developing RBCs

2. Inflammatory cellular products also impair the production and action of erythropoietin

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ACD - PathophysiologyACD - PathophysiologyThe main feature of ACD is sideropenia in

the face of abundant iron storesBM 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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Laboratory Diagnosis of ACDLaboratory Diagnosis of ACDPB picture shows mild anemia (Hgb 9-11

g/dL) without reticulocytosisNormocytic, normochromic RBCsInflammatory process may show increased

WBCs and/or thrombocytosisIron studies show low serum iron and

TIBC, Transferrin saturation may be normal or low and ferritin is usually increased

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Laboratory Diagnosis of ACDLaboratory Diagnosis of ACDFailure to incorporate iron into heme

causes elevated FEPBM 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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Laboratory Diagnosis of ACDLaboratory 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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Sideroblastic AnemiasSideroblastic 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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Sideroblastic AnemiasSideroblastic 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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Sideroblastic AnemiasSideroblastic AnemiasIron 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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Lead PoisoningLead 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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Iron OverloadIron 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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Iron OverloadIron 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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Iron OverloadIron OverloadIron 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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Iron OverloadIron OverloadHH 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