Step 4

1. Diagnosis of case

Iron Deficiency Anemia

Iron deficiency anemia (IDA) has variably decreased hemoglobin caused by

insufficient iron. In advanced cases the anemia is severe and markedly

microcytic and hypochromic, but early on, hemoglobin and mean corpuscular

volume (MCV) are only minimally decreased.

CLINICAL FEATURES

A. Secondary to the Anemia Itself

Because the anemia is insidious in onset, compensatory mechanisms usually

prevent symptoms' until the hemoglobin falls to the range of 8 g/dL. Coexisting

disease of the cardiopulmonary system may act jointly with less advanced

anemia to produce symptoms typicoafl more severe anemia. When anemia is

sufficiently advanced to be solely responsible for symptoms, the physical

examination usually reveals pallor, and, occasionally, koilonychia, angular

stomatitis, and glossitis, as well as splenomegaly.

B. Secondary to the Underlying Condition

Iron deficiency anemia results from three abnormalities affecting iron: loss

from abnormal bleeding, deficient diet, and malabsorption.

1. Blood Loss

Blood loss is the most common causeo f IDA in adults livingin developed

countries. Gastrointestinal blood loss is the most frequent cause in males and

postmenopausal females. Heavy menstrual bleeding is a frequent cause of IDA

in women of child-bearing age. Pregnancy, which requires approximately 1000

mg of iron, is also a common cause. Intestinal parasites, such as hookworms

and schistosomes, often cause IDA in underdeveloped regions, but are rarely

found in developed countries.

2. Deficient Diet

In a broad sense, iron deficiency develops when intake does not keep pace with

utilization and loss of iron. Worldwide, the most common cause is a low

content of dietary iron, especially in readily absorbable forms such as in meat.

In developed countries, dietary inadequacy is uncommon except when it is

relative to increased need, as in the premature infant. Term infants may also

develop iron deficiency, especially when bottle fed. Female adolescents, with

increased need for iron because of both rapid growth and onset of menses, have

a relatively high incidence of iron deficiency.

3. Malabsorbtion

Malabsorption is an uncommon cause of IDA. Some patients with the short

bowel syndrome, nontropical sprue, or a history of gastrectomy cannot absorb

iron normally. Increased blood loss contributes to their anemia, and the

majority have symptom a history of gastrointestinal disease.

2. Why diagnosis of case about iron deficiency anemia

When the anemia is severe, the routine blood count providest he information

needed for diagnosis, and additional studies are needed only to establish the

etiology of the deficiency. The medical history and physical findings relative to

the gastrointestinal tract and, in women, to the genital tract will most often

reveal the reason for anemia. Endoscopic and/or radiographic evaluation of the

gastrointestinal tract is frequently required to reveal the source of blood loss.

When the anemia is mild to moderate, more extensive evaluation is necessary

to establish that iron deficiency is its cause. Serum ferritin is the key test for

making this determination, but the acute-phase reaction may interfere with its

interpretation, necessitating a bone marrow examination or a trial of iron

therapy to establish the presence of iron deficiency.

LABORATORY FINDINGS

Laboratory tests are essential for detecting or confirming anemia and for

determining that it is caused by iron deficiency, but they are of limited value in

ascertaining the deficiency’s cause. The latter is determined by the history and

physical examination, supplemented by endoscopic and radiographic

evaluation of the gastrointestinal tract. Followinigs a discussion of laboratory

tests commonly used for evaluating IDA.

A. Hemoglobin Level

In severe, chronic iron deficiency, the hemoglobin may be as low as 3-4 gldL.

The degree of anemia is related directly to the severity and duration of

deficiency, and the spectrum of hemoglobin values ranges downward from

normal. Hemoglobin is the key test for detecting the presence of anemia and

for following its response to treatment.

B. Red Cell Indices, Including RDW

The MCV is of great importance in determining that iron deficiency is causing

anemia. As with hemoglobin, the MCV varies downward from normal,

depending on the severity of anemia. When hemoglobin is in the 3 to 4-gldL

range, the MCV will be 50-60 fl. A discordance between the two values, for

example, a hemoglobin of 6 g/dL associated with an MCV that is only mildly

decreased, is indicative of IDA complicated by another process, such as

significant acute blood loss, or of an entirely different type of anemia. The

MCH and MCHC are less important, especially the latter. Most laboratories

use automated cell counters that do not detect decreased MCHC until there is

marked hypochromia and microcytosis. The RDW appears not to be a valuable

discriminator between IDA and other causes of microcytic anemia. A normal

value tends to exclude IDA, but an elevated value lacks specificity.

C. Reticulocyte Count

The reticulocyte counti s not an important test in the evaluatiofn IDA. It is

usually essentially normal, as it is in the disorders from which iron deficiency

must be differentiated.

D. White Cell and Platelet Counts

There are no characteristic or diagnostically important changes in white cells or

Elevated white cell and platelet counts occasionally occur, and, rarely, the

latter rnillion. There may also be thrombocytopenia, which in rare cases may

be severe.

E. Red Cell Morphology

Microcytosis, anisocytosis, poikilocytosis, and hypochromia are readily seen in

the peripheral blood smear of individuals with moderate to marked IDA.

However, because of inconsistent and inaccurate interpretationof the blood

smear, as well as the superior sensitivity and accuracy of automated

determination of red cell indices, morphologic findings do not contribute

significantly to the accurate diagnosis of IDA.

F. Serum Ferritin

In a recent meta-analysis, Guyatt and associates found serum ferritin to be

much more powerful than all other blood tests for diagnosing iron deficiency.

In the absence of disorders that produce an acute-phase reaction, there is

excellent correlation between the serum ferritin level and iron stores.

Unfortunately, conditions such as malignancy, infection, and noninfectious

inflammatory disorders cause serum ferritin to act as an acute-phase reactant

producing “false” elevations that make interpretation difficult. With very rare

exceptions, a subnormal ferritin level indicates absent iron stores, eveni f the

acute phase reactioni s present. When the latter is occurring, values in iron

deficiency may range upward to 100 ng/nL, with decreasing likelihood of iron

deficiency as the value approaches 100.

G. Serum Iron, Transferrin, and Transferrin Saturation

Before the serum ferritin test was available, these were the preferred blood

tests for assessing iron stores. However, the acute-phase reaction decreases

serum iron to less than normal and also frequently decreases transferrin. These

tests have less diagnostic power than the serum ferritin and should no longebr e

used to test for iron deficiency, especially in sick, hospitalized patients.

H. Serum Transferrin Receptor

Elevated concentrations of serum transferrin receptor are found in both iron

deficiency and erythroid hyperplasia. There is indication that this test, which is

currently used only in

research settings, may help evaluate iron stores when the acute-phase reaction

is present.

I. Red Cell Protoporphyrin

Iron deficiency,l ike lead poisoning, increases redce ll protoporphyrin. The

availability of accurate and easily operated hematoflourometers has increasedt

he use of this test in screening for these two conditions. However, redc ell

protoporphyrin levels lack the sensitivity and specificity of serum ferritin for

iron deficiency.

J. Fecal Occult BIood

Because gastrointestinal bleeding frequently leads to anemia, testing the stool

for blood has a time-honored place in the investigation of IDA. However, many

foods, such as meat, broccoli, and bananas, as well as liquid stool samples and

oral iron therapy, may cause false positive reactions. Administration of

ascorbic acid, as well as degradation of hemoglobin when there is upper

gastrointestinal bleeding, may cause false negative reactions. In addition, many

lesions probably bleed only intermittently, producing negative reactions on

stools from nonbleeding intervals. For these reasons, the sensitivity and

specificity of tests for occult blood are relatively low. Negative tests should not

be a deterrent from endoscopic or radiographic evaluation of the

gastrointestinal tract in patients with unexplained microcytic anemoiar other

indications for such examination.

K. Bone Marrow Examination

Erythrocytic hyperplasia and deficient hemoglobinization of red cell precursors

are usually found in the marrow, particularly in more advanced cases.

However, these changes have only modest diagnostic significance, and the

pivotal finding is the absence of marrow iron stores.

This is the “gold standard“ for determining iron deficiency. Marrow

examination is not required for most patients but should be carried out when

the diagnosis is in doubt, especially when the serum ferritin has an equivocal

value, or when a trial of iron therapy fails. Normal infants and children have

little or no stainable iron stores, and evaluation of marrow iron does not

distinguish depleted from normal stores.

3. Differential Diagnosis

DIFFERENTIAL DIAGNOSIS

A. Anemia of Chronic Disease

IDA and anemia of chronic disease (ACD) are both very common, and they

frequently coexist. Also, microcytosis is frequent in ACD. Therefore, it is often

necessary to determine whether a patient has IDA, ACD, or both.

Differentiation hinges on the serum ferritin Ilenv ae l .p atient who may have

both IDA and ACD, a value below the usually quoted normal, 10-12 ng/nL,

confirms iron deficiency. If, as is more likely, the level is in the normal range,

the closer it is to the lower limit of normal, the more likely is iron deficiency.

Some authors state that a normal RDW argues against iron deficiency, because

the test has a high sensitivity for IDA. However, the preponderance of evidence

suggests that the test lacks sufficient sensitivity to supplement the diagnostic

power of serum ferritin. In some cases a clear-cut distinctioncan not be madoen

the basis of clinical and laboratory findings, and a trioafl iron therapy or a bone

marrow examination may be required.

B. Thalassemia

Heterozygous alpha and beta thalassemia are common microcytic anemias. The

combination of low normal to slightly decreased hemoglobin, high normal to

slightly increased red cell count, moderately decreased MCV, and target cells

is characteristic of thalassemia minor. In iron deficiency when the hemoglobin

is comparable to that typical of thalassemia minor, the MCV is usually less

abnormal. Serum ferritin and hemoglobin A2 levels usually suffice to make the

distinction.

C. Hemoglobinopathy

Hemoglobin E, common in Southeast Asians, causes microcytosis thaits mild

in heterozygotes and marked in homozygotes (17). Heterozygotes are usually

not anemic and homozygotes only mildly so. Hemoglobin electrophoresis is

diagnostic.

D. Lead Poisoning

In the past, lead poisoning was considered in the differential diagnosis of

microcytic anemia, but it is now thought that both anemia and microcytsis are

secondary to coexisting iron deficiency, which is common in underprivileged

children, a group in which plumbism is often found.

4. Pathophysiology of iron deficiency anemia

PATHOPHYSIOLOGY

A. Iron Metabolism

The major portion of body iron is in hemoglobin, myoglobin, and various

enzymes. Nearly of the remainder is in storage in the reticuloendotheli~

system, primarily in the bone marrow, liver, and spleen.

1. Absorption

Normally, dietary absorptionis limited to the amounto f iron necessary to

produce hemoglobin, myoglobin, and enzymes, to compensate for losses, and

to build stores. When losses increase or there are other causes of increased

need, absorption may not keep pace because it can increase only modestly.

2. Loss

Adults daily lose approximately 1 mg of iron, mainly in desquamated

epidermal, urinary, and gastrointestinal cells. Menstrual bleeding adds, on

average, slightly more than 1 mg to the daily loss, as does lactation.

3. t r a n s p ort

Transferrin is the primary vehicle for transporting iron entering the plasma.

Essentially all proliferating cells have on their surfaces transferrin receptors

whose affinity increases with the latter’s iron content and whose synthesis and

release into the blood increases with decreasing availability of iron. Erythroid

precursors and hepatic and placental cells have more receptors than other cells.

4. Storage

Ferritin is the primary storage protein for iron, and its production and cellular

content, as well as the amount circulating in plasma, are increased by

increasing amounts of cellular iron. Ferritin, present in essentiallya ll cells,

readily gives up iron and serves as the storage compartment for cellular

utilization. Hemosiderin, a more stable storage form, holds most of the iron in

the reticuloendothelial system’s macrophages.

B. Progression of Iron Deficiency

When absorption does not keep pace with utilization and loss, iron stores are

used. As stores become depleted, the individual passes through three stages of

iron deficiency.

1. Latent Stage

Iron stores are depleted, and marrow contains no stainable iron. However,

hemoglobin production has not yet decreased, and there is no anemia or

microcytosis. Serum ferritin, reflecting body iron stores, is decreased. Serum

transferrin receptors, serum iron, transferrin, transferrin saturation, and red cell

protopophyrin are normal.

2. Early Stage

As the imbalance between absorption and need continues, insufficient iron is

available for hemoglobin synthesis, and the various markers of deficiency

begin to be established. The hemoglobin decreases through the normal range

into the subnormal. Red cells being produced are smaller and have decreased

content of hemoglobin and increased zinc protoporphyrin.

However, early in this stage, because abnormal cells are mixed int he

peripheral blood with a much larger number of normal cells, routine studies of

red cell parameters continue to be normal. Therefore, especially if the patient’s

baseline MCV is in the upper portion of the normal range, early IDA can be

normocytic. Serufemrr itin, already below normal during latent deficiency, can

undergo no further measurable decrease, and thuiss not helpful in determining

the degree of deficiency. Serum transferrin receptors, however, become

increased in the early stage of iron lack and progressively increase as the

deficiency worsens.

3.Established Stage

As the deficiency progresses, under the stimulation of increasing amounts of

erythropoietin, erythroid precursors are more numerous in the marrow, and the

lack of iron causes the more mature forms to have visibly less cytoplasm that

has deficient hemoglobinization. Anemia worsens, and progressively smaller

red cells with lesser amountosf hemoglobin become more numerous in the

peripheral blood. As the duration and severity of deficiency increase, and as

more of the previously produced normal cells become senescent and are

removed, the RDW increases and red cell histogram widens. The MCV and

MCH decrease and become progressively more abnormal, in proportion with

the decrease in hemoglobin. Likewise, there is a proportionate increase in

serum transferrin receptors.