**3. Differential diagnosis of microcytic anemia**

Students are traditional taught that the differential diagnosis of microcytic anemia includes five possible conditions:


248 New Advances in the Basic and Clinical Gastroenterology

There have been numerous reviews on the evaluation of anemia and microcytic anemia in children (Jain & Kamat 2009, Janus & Moerschel 2010). Although these reviews attempt to be comprehensive, they tend to be overly simplistic and misleading. Specifically with regard to microcytic anemia, the impression given is that nutritional deficiency is the most frequent cause of iron deficiency and hence microcytic anemia. Although this may be true for mild anemia, it is certainly not true for severe anemia, where blood loss is far more common. While a child with a hemoglobin of 11 g/dL and mild microcytosis may have a lack of sufficient iron in his or her diet, a hemoglobin of 5 g/dL and MCV of 55 fL cannot be due to nutrition alone. Anyone at any age with such values requires investigation for a serious condition and should not be treated with iron supplementation alone. To assume that most cases of microcytosis should be treated with supplemental iron alone is to miss the

Iron deficiency and iron deficiency anemia affect a large proportion of people worldwide (Beard & Stoltzfus, 2001; Benoit 2001; Stoltzfus, 2001). According to the Fourth National Health and Nutrition Examination Survey (NHANES IV), iron deficiency without anemia exists in 7% of toddlers aged 1 to 2 years, 9% of adolescent girls, and 16% of women of childbearing age, (Looker, 2002) a true public health concern. Unfortunately, studies of the prevalence of iron deficiency anemia use arbitrary definitions of anemia and iron deficiency, such as a hemoglobin less than 11 (Eden & Mir, 1997). There is often no attempt to separate iron deficiency based on severity, so that the true incidence of *severe* iron deficiency anemia

It must be remembered that iron deficiency and iron deficiency anemia are somewhat distinct, but overlapping and related disorders. Although confirmatory studies are lacking, it is probably true that the greatest cause of iron deficiency worldwide and in the United States is nutrition, i.e. lack of sufficient iron in the diet, and the greatest cause of iron deficiency *anemia* worldwide and in the United States is slow gastrointestinal bleeding. Statistics stating the leading causes of these conditions can easily mislead the practitioner, since the epidemiology of iron deficiency and iron deficiency are different, and also varies by age, gender, socioeconomic status and geography. Worldwide, and especially in poor countries, infestation by hookworm (mostly Necator americanus and Ancylostoma duodenale) is the leading cause of gastrointestinal blood loss leading to iron deficiency and iron deficiency anemia. Infestation by Trichuris trichiura, the cause of trichuriasis (whipworm) infection is common throughout many parts of the world, and symptomatic infestations leading to iron deficiency or growth retardation preferentially affect children between 2 and 10 years of age. By contrast, in the United States, parasitic infestation has become distinctly rare due to improved sanitation and the fact that most children in the U.S. now wear shoes when outdoors. In the United States, cultural differences in feeding

practices affect the incidence of iron deficiency anemia (Kwiatowski, 1999)

The association between iron deficiency anemia and impaired neurocognitive function is well established, and is independent of psychosocial and environmental factors. The association is especially strong in young children and infants (Oski, 1979). There is evidence

**2.2 Health effects of iron deficiency** 

opportunity and the necessity of the proper workup for significant pathology.

**2.1 Epidemiology of iron deficiency in children** 

is unknown.


Figure 1 shows a general schema for distinguishing these disorder based on RBC size (MCV) and hemoglobin level. The figure is not meant to show the exact values for these disorders, but to emphasize the relative values and emphasizes their overlap. After considering some of the disorders that overlap with iron deficiency, this chapter will focus on the severe anemias that are severely microcytic, i.e. those that are most likely due to iron deficiency. Note that lead poisoning is not included in the figure because as explained below it is now considered more of a consequence than a cause of iron deficiency; sideroblastic anemia is also not seen because it is not a distinct condition and thus shows considerable heterogeneity in hemoglobin and MCV. Likewise, bone marrow failure syndromes such as Diamond-Blackfan anemia, the erythropoietin deficiency of end stage renal failure, transient erythroblastopenia of childhood, and leukemia encompass a wide variety of separate disorders with different combinations of MCV and hemoglobin, but none of these are microcytic.

It is important to keep in mind that the presence of one disorder does not exclude others. For example, iron deficiency may occur in patients with thalassemia, and patients may have concomitant acute and chronic bleeding. Also, the relationship is altered by therapy; hence patients who have been partially or inadequately treated may have values that do not fit the expected relationships.

From a practical sense, when considering the above five disorders, the severely microcytic anemias limit this differential for the most part to the top two, and further considering only those that are severely anemic to a large extent eliminates all but the first. As we shall see, a large part of microcytic anemia in children, as in adults, and certainly the severe clinically important cases, is due to iron deficiency anemia. As will be discussed, once iron deficiency

A Case Based Approach to Severe Microcytic Anemia in Children 251

after the event, providing the patient survives and has adequate iron stores, i.e. there is not coexistent chronic blood loss. Therefore the anemia of acute blood loss is due to blood loss, while the anemia of iron deficiency is due to iron loss, and is in fact a bone marrow failure

Signs and symptoms of acute blood loss are very different from those of chronic blood loss. Acute blood loss leads to volume depletion and can rapidly progress to tissue hypoperfusion and shock, while the slow onset of anemia that occurs with chronic blood loss allows hemodynamic compensation. Children especially can tolerate extremely low hemoglobins if gradual in onset, without cardiac decompensation and no end organ effects. These children will appear pale, and have compensatory tachycardia, and may have dyspnea and headache on exertion, but very small children may have no signs other than pallor and mild fussiness. Some children will appear "yellow" due to underlying skin pigmentation, especially if the diet includes yellow vegetables, but actual jaundice is easy to

We will now discuss in some detail the five traditional causes of microcytic anemia, using

The sideroblastic anemias are a heterogeneous group of congenital and acquired bone marrow disorders defined by the presence of pathologic iron deposits within the mitochondria of erythroid precursors. The anemia may be mild, moderate or severe and may be normocytic, microcytic, or macrocytic and is typically characterized by a relative reticulocytopenia (Flemming, 2009). There are several known and incompletely characterized congenital causes, but all are rare including atransferrinemia, hypotranferrinemia (Shamsian et al., 2009), and others (Iolascon et al., 2009). Acquired causes include a variety of toxic exposures, drugs, and myelodysplastic syndromes, as well as copper deficiency. Many of these, although included in a full discussion of anemia and microcytic anemia, do not need to be considered in this chapter because they only rarely present as a severe anemia that is severely microcytic. Copper deficiency, for example is extremely rare, is usually normocytic, and the major manifestations are neurologic rather

A 10 year old boy was referred to pediatric hematology clinic for anemia occurring on a previous blood test. Two months earlier he had been hospitalized briefly for a high fever and rash. While in the hospital, a CBC showed a mild microcytic anemia (hgb 10.0 g/dL (normal 11.9-15.4 g/dL), MCV 75 fL (normal 80-95 fL). He recovered well and was subsequently discharged. He had since been well, with no subsequent fevers, and no weight loss or night sweats. He had had no increased fatigue or exercise intolerance. His family history was negative for any hematologic disorders or malignancies. He had no chronic

In clinic, he appeared healthy, cooperative and in no distress. His skin showed no rash, bruises, jaundice, or pallor. He had no lymphadenopathy, scleral icterus, or conjunctival pallor. His lungs were clear with no wheezes, and his heart sounds were normal with no

medical conditions, took no medications, and had no known drug allergies.

syndrome limited to red cells due to lack of substrate (iron).

exclude due to the lack of scleral icterus.

**3.3 The anemia of "chronic disease" (Case 1)** 

some specific cases to illustrate.

**3.2 Sideroblastic anemia** 

than hematologic.

Fig. 1. Approximate relationship of anemias according to hemoglobin and red cell size (MCV)

is determined to be likely, the cause of the deficiency must be determined, and it is important for the clinician to distinguish blood loss from other causes. This list of causes varies depending on the age of the patient, the severity of the anemia and the severity of microcytosis. The chapter will outline a more thorough differential for all causes, leading towards a proper diagnosis before initiating treatment. We will emphasize that iron therapy alone is not adequate therapy; as such treatment alone will leave the cause of the anemia undiagnosed and untreated.

#### **3.1 Acute blood loss**

Since iron deficiency anemia is almost always due to chronic blood loss, the distinction between acute and chronic blood loss must be made. While both lead to anemia, the causes as well as the signs and symptoms are profoundly different between the two. As to the cause, acute blood loss can occur externally by any route or internally into practically any space, including intracranial, intrathoracic, retroperitoneal and abdominal. Isolated acute blood loss is normocytic, with a reticulocyte count that is not elevated until several days after the event, providing the patient survives and has adequate iron stores, i.e. there is not coexistent chronic blood loss. Therefore the anemia of acute blood loss is due to blood loss, while the anemia of iron deficiency is due to iron loss, and is in fact a bone marrow failure syndrome limited to red cells due to lack of substrate (iron).

Signs and symptoms of acute blood loss are very different from those of chronic blood loss. Acute blood loss leads to volume depletion and can rapidly progress to tissue hypoperfusion and shock, while the slow onset of anemia that occurs with chronic blood loss allows hemodynamic compensation. Children especially can tolerate extremely low hemoglobins if gradual in onset, without cardiac decompensation and no end organ effects. These children will appear pale, and have compensatory tachycardia, and may have dyspnea and headache on exertion, but very small children may have no signs other than pallor and mild fussiness. Some children will appear "yellow" due to underlying skin pigmentation, especially if the diet includes yellow vegetables, but actual jaundice is easy to exclude due to the lack of scleral icterus.

We will now discuss in some detail the five traditional causes of microcytic anemia, using some specific cases to illustrate.
