**4. Iron deficiency**

As is evident above, cases of microcytic anemia that are NOT due to iron deficiency are usually easy to distinguish. The remaining cases in this chapter are all due to iron deficiency. With two notable exceptions, severely microcytic severe anemias in children are due to chronic gastrointestinal blood loss. Figure 2 shows the relative frequencies of the major causes of iron deficiency anemia to be explained in the following sections, illustrating the 2 major sites of blood loss (gastrointestinal and vaginal) and the two major gastrointestinal etiologies (blood loss and iron malabsorption).

Fig. 2. Relative frequencies of causes of iron deficiency anemia (not to scale)

Because so much of the body's iron resides in hemoglobin, anemia is one of the first signs of iron deficiency, but anemia is actually a late stage of iron depletion. Iron deficiency leading to anemia is a continuum, but there are three recognized phases:


With adequate treatment, these stages occur in reverse, i.e. the anemia resolves before adequate iron stores are replenished.

Several pediatric cases will be presented and discussed to illustrate the importance of the gastrointestinal tract in severe iron deficiency anemia. However, the initial case is of severe microcytic anemia occurring in an adult to make the connection between microcytic anemias and gastrointestinal blood loss clear.

#### **4.1 Severe microcytic anemia in an adult (Case 3)**

A 63 year old male presented to his physician with complaints of fatigue and shortness of breath, progressive over several weeks. The physician noted that the patient looked pale and ordered a complete blood count. The CBC revealed a hemoglobin of 5.9 g/dL and an MCV of 59 fL. The physician correctly interpreted this as a severe microcytic anemia, and that this anemia was of relatively recent onset. The physician considered transfusions and a prescription for oral iron as therapy for the anemia. However, upon considering the etiology of the anemia with the above history, he knows that the microcytosis is not consistent with a lesion leading to acute blood loss. Chronic blood loss is the only possibility, and that blood loss MUST be gastrointestinal. He referred the man to a gastroenterologist for a thorough investigation.

#### **4.1.1 Discussion**

254 New Advances in the Basic and Clinical Gastroenterology

As is evident above, cases of microcytic anemia that are NOT due to iron deficiency are usually easy to distinguish. The remaining cases in this chapter are all due to iron deficiency. With two notable exceptions, severely microcytic severe anemias in children are due to chronic gastrointestinal blood loss. Figure 2 shows the relative frequencies of the major causes of iron deficiency anemia to be explained in the following sections, illustrating the 2 major sites of blood loss (gastrointestinal and vaginal) and the two major

gastrointestinal etiologies (blood loss and iron malabsorption).

Fig. 2. Relative frequencies of causes of iron deficiency anemia (not to scale)

to anemia is a continuum, but there are three recognized phases:

hemoglobin level. The serum ferritin level will be low.

adequate iron stores are replenished.

and gastrointestinal blood loss clear.

affected, resulting in anemia, microcytosis and hypochromia.

Because so much of the body's iron resides in hemoglobin, anemia is one of the first signs of iron deficiency, but anemia is actually a late stage of iron depletion. Iron deficiency leading

1. *Prelatent iron deficiency* occurs when tissue stores are depleted, without a change in

*2. Latent iron deficiency* occurs with depletion of iron from the reticuloendothelial system. TIBC increases and the serum iron level will fall as newly produced erythrocytes will be

3. *Iron deficiency anemia* occurs when a substantial portion of the erythrocyte population is

With adequate treatment, these stages occur in reverse, i.e. the anemia resolves before

Several pediatric cases will be presented and discussed to illustrate the importance of the gastrointestinal tract in severe iron deficiency anemia. However, the initial case is of severe microcytic anemia occurring in an adult to make the connection between microcytic anemias

iron deficient, but the overall hemoglobin level and MCV remain normal.

**4. Iron deficiency** 

For this patent, while several more benign lesions leading to chronic blood loss can be responsible, the lesion must be found, as colon cancer must be considered highly likely until proven otherwise. The sequence of events is therefore clear: The patient has developed a lesion in his GI tract that has been losing blood slowly over at least several months. Since the blood loss is relatively slow, the patient's bone marrow easily makes up for the anemia at first, but eventually stores of iron are depleted from his liver and other sites. At that point his anemia becomes more severe and begins to be microcytic, until the anemia itself becomes severe enough to cause the complaints that lead him to seek help from his physician. In retrospect the patient may or may not have noticed the typically black or tarry stools, depending on the rate of bleeding, and in fact the stool may not even consistently test positive for blood since the bleeding is often intermittent. In fact, testing the stool for blood in such a case is not necessary, as there can be no other cause of this type of anemia in this man but gastrointestinal bleeding. A negative stool test is in no way reassuring; this man must be referred to find the specific lesion. Transfusion and iron therapy do not treat the bleeding. It should even be stated that in such a case of anemia the hematologist plays no role. At any age the more severe the anemia and the microcytosis, the more likely that blood loss rather than a nutritional cause is the responsible mechanism.

The following pediatric cases will use the same concepts illustrated in the above case to emphasize the role of the gastroenterologic system in the etiology and therapy of severe microcytic anemias.

#### **4.2 Milk enteropathy (Case 4)**

A 14 month old boy presented to his pediatrician for a one year well child checkup. At the visit however his parents explained to the pediatrician that he had been pale for about the last month or so, not feeding well, and had some pica like behaviors. He had recently been more fussy and was sleeping poorly. They denied any jaundice, change in bowel or urinary habits or breathing difficulties. They denied bloody or black stools. They reported poor feeding when offered a variety of foods, and until very recently his diet relied heavily on milk, and he would typically go through a gallon every other day. The family lived in an older apartment with chipping paint that the parents admitted the child sometimes peeled from the walls. His growth and development had otherwise been normal. He took no

A Case Based Approach to Severe Microcytic Anemia in Children 257

second year of life for some children, so that *excessive* whole milk given to some toddlers causes an enteropathy with enough chronic blood loss to create severe iron deficiency anemia (Buchanan, 1999; Kwiatowski et al., 1999). For these severe anemias the cause is often misunderstood to be "nutritional" due to the above mechanisms of poor iron bioavailability and absorption. While inadequate iron in the diet might lead to a mild iron deficiency, the severe anemia in the case above can only be caused by chronic gastrointestinal bleeding. As for the adult, testing for occult blood is not needed. The etiology of the blood loss is exposure of the gut to the excessive milk protein. Treatment includes iron supplementation, but the enteropathy must be treated as well, by removing the excess milk from the diet. Transfusion therapy is usually not needed regardless of how low the hemoglobin, unless signs of decompensation such as heart failure are present, and in those cases must be done cautiously. A reasonable approach in these severe cases is to stop the milk entirely and provide therapeutic iron. After several weeks, when labs indicate improvement in the hemoglobin from the therapeutic iron, milk can be restarted, in

Compliance with iron therapy can be an issue, especially in this age group. Intravenous iron can be considered in these cases, or other forms of iron such as heme iron (Proferrin®, Colorado Biolabs, Inc.), (Nissenson et al. , 2003) that can be more palatable and well

A 14-year-old male was seen in pediatric hematology clinic in consultation for anemia. A month earlier he had had two episodes of pneumonia and bronchitis that were treated with antibiotics. He then started complaining of fatigue, prompting a CBC that revealed

The patient reported a long history of diarrhea once or twice a day, associated with bloating and cramping, especially after eating but could not relate it to any particular food. He denied any history of bloody stools, hematuria, or mucosal bleeding. There was no history of fevers, weight loss, cough, or difficulty breathing, and the rest of the review of systems was negative. His development had been normal. He had had no previous hospitalizations or surgeries. His immunizations were up-to-date. His only current medication was iron 325

The patient had four healthy sisters. His mother had a history of iron deficiency with heavy periods but there was no other history of anemia in the family. His paternal grandfather has

On exam his weight was 59.5 kg, between the 25th and 50th percentiles for age. His exam was mostly normal, with some voluntary guarding but no obvious abdominal tenderness, masses or organomegaly. Abdomen was nondistended, soft, nontender, with active bowel sounds. His extremities showed full range of motion of all joints, nontender, and well

His CBC was normal except for a microcytic anemia (hgb 10.2 g/dL, MCV 67.1 fL), and a mild thrombocytopenia, all consistent with iron deficiency anemia. Hemoglobin

a history of diverticulitis and a cousin of his father had a history of Crohn's disease.

absorbed with fewer side effects, but efficacy studies in children are lacking.

microcytic anemia that was subsequently shown to be due to iron deficiency.

moderate amounts with meals.

**4.3 Crohn's disease (Case 4)** 

mg PO daily started a week prior.

perfused, and his neurologic exam was grossly intact.

electrophoresis was normal and his blood smear was normal.

medications and had no known allergies. He had three healthy half siblings. His mother was of German ancestry and had been anemic herself in the past. The father also denied any significant family history.

In clinic, the patient was alert and active but fussy during the exam. He was markedly pale, with no jaundice, bruising, petechiae, or rash. His tympanic membranes and oropharynx were clear. He had no adenopathy. His lungs were clear with no wheezes, and heart sounds were normal with no murmurs. His abdomen was soft and nontender with no hepatosplenomegaly. His extremities were well perfused with no edema.

Blood work was remarkable for a hemoglobin of 4.7 g/dL and MCV of 63 g/dL, a severe (and severely microcytic) anemia. His CBC was otherwise unremarkable except for red cell morphologic abnormalities consistent with severe iron deficiency. A serum lead level was only 4 mcg/dL.

The patient had a severe microcytic, hypochromic anemia, but was well compensated with no sign of heart failure. His parents were instructed to stop his milk entirely and he was started on therapeutic iron supplements. They were instructed that concomitant intake of orange juice would aid absorption of the iron. Follow-up labs were planned to assure his anemia was improving, but the plan was for him to continue taking the iron for several months after his anemia resolved, in order to replenish his iron stores. Milk could be added back to the diet, but only with meals, as soon as the anemia had begun to improve.
