**5.1.1 Discussion**

258 New Advances in the Basic and Clinical Gastroenterology

The patient was referred to Pediatric Gastroenterology where endoscopic exam showed mild esophagitis, chronic gastritis, a normal duodenum, lymphoid aggregates and a focal granuloma in his colon, consistent with Crohn's disease. Medical treatment was successful

This boy presented with an acquired moderate anemia that was severely microcytic. As with the previous two cases, chronic slow gastrointestinal bleeding is the likely cause, leading to iron loss, eventually leading to depletion of stores of iron and the characteristic anemia. A full discussion of the pathophysiology and therapy of Crohn's disease and inflammatory bowel disease is beyond the scope of this chapter but the hematologic manifestations are likely due to the slow blood loss, although the anemia of inflammation may play a role as

In all three of these cases, the microcytic anemia was due to slow gastrointestinal blood loss, although the specific cause of the blood loss was different, and to a large extent age

One common feature of the above cases is that although all presented with a severe microcytic anemia, none of the underlying causes were fundamentally hematologic in nature. Therefore in the overwhelming majority of cases of microcytic anemia, these patients have a gastrointestinal cause (slow gastrointestinal blood loss) and need to be referred to a gastroenterologist for diagnosis of the underlying cause. There are two exceptions to the above generalizations. One is a special case of non gastrointestinal blood loss, and the other is due to a defect in iron absorption, although even that cause is still gastrointestinal. These

A 12-year-old female was referred to pediatric hematology clinic for a possible bleeding disorder. She had had heavy menstrual periods since menarche 6 months previously. She had been admitted to a local community hospital 4 months earlier at which time she was

in alleviating his symptoms and his anemia.

**4.4 Iron deficiency from gastrointestinal bleeding – Summary** 

Other causes, e.g. Meckel's diverticulum

Other causes, e.g. AV malformation, ulcer

**Toddler** Excessive whole milk ingestion

**School age/Teen** Inflammatory bowel disease

Menorrhagia

**Adult** Colon Cancer

Other causes, e.g. ulcer

exceptions are illustrated in the two cases below:

**5.1 Menorrhagia (Case 6)** 

**5. Iron deficiency not due to gastrointestinal bleeding** 

dependent. The approach to the underlying cause is therefore age dependent:

**4.3.1 Discussion** 

well.

As demonstrated by the first three cases above, acquired severe microcytic anemias are almost always due to chronic gastrointestinal blood (i.e. iron) loss. One notable exception is demonstrated in this case, in which the route of bleeding is vaginal. There is a common misconception that menstruating females have lower average hemoglobin levels because of normal menstrual bleeding. While there is overlap between the normal ranges of males and female hemoglobins, the lower average values in females are due to lower testosterone levels, not vaginal bleeding. Hence adults have higher hemoglobins than children, and males have higher values than females. Normal menstruation can lead to iron deficiency but not anemia; therefore actual anemia implies abnormal bleeding. Abnormal bleeding can be an acute vaginal hemorrhage from a single or a few heavy periods, but it is chronic bleeding from many heavy periods that leads to iron deficiency anemia, as in this case.

As most cases of severe microcytic anemia have a GI cause, a gastroenterologist rather than a hematologist should be involved. Dysfunctional uterine bleeding requires a gynecologic workup, but a proportion of these cases have an underlying bleeding disorder, so it is these cases that should also be referred to a hematologist for an adequate workup for conditions such as von Willebrand's disease and platelet function disorders. Women with menorrhagia, especially if present since menarche, have an incidence of von Willebrand's disease of around 13%, considerably higher than the general population incidence of 1% to 2% (Kadir et al., 1998; Lukes et. al., 2005). For the most part however, the management involves oral contraceptive pills. It should be noted that if there is not a convincing history of several heavy periods, a gastrointestinal cause should still be sought.

Other causes of chronic bleeding and iron loss leading to iron deficiency anemia are rare and usually obvious from the history. Iron deficiency and iron deficiency anemia can result from pulmonary hemosiderosis and from renal bleeding in Berger's disease. These rare

A Case Based Approach to Severe Microcytic Anemia in Children 261

In general, the more cell lines that are depressed, and the lower the values, the more likely is an underlying marrow disease. Hence, pancytopenia (neutropenia, anemia, and thrombocytopenia) makes leukemia more likely while an isolated single cytopenia (neutropenia, anemia, *or* thrombocytopenia) makes a peripheral disorder outside the marrow more likely. If leukemia or a primary marrow failure is suspected, referral to a pediatric hematologist/oncologist should be made promptly for further testing, including a marrow evaluation. An isolated severe microcytic anemia is not consistent with leukemia and indicates slow blood (i.e. iron) loss (gastrointestinal or vaginal), or in the case of celiac disease, lack of iron absorption. The severe depletion of iron leads to marrow failure in a sense, in that the marrow is unable to complete heme synthesis. Despite the marrow "failure," further marrow evaluation of marrow function is not part of the evaluation, as the

In iron deficiency anemia a clue to otherwise normal marrow function is often provided by a "left shift" of the other cell lines; leukocytosis, elevated neutrophil count, increased bands and other immature forms, and an elevated platelet count with large platelets. The reticulocyte count is often only mildly elevated, reflecting the lack of iron substrate. Hemolytic anemias such as sickle cell disease, autoimmune hemolytic anemia and hereditary spherocytosis also shift cell lines to the left, but are not microcytic and present with a much higher reticulocyte count. A high reticulocyte count makes a hemolytic anemia likely, especially if the anemia is normocytic or mildly macrocytic. B12 and folate deficiency are not microcytic and are considerably rarer than iron deficiency. The iron panel is usually consistent with other studies, but serum iron may be misleading, as recent ingestion of iron may elevate the value. Ferritin, as an acute phase reactant, may also be elevated in a deficiency state, but low values always represent iron deficiency, and occur in no other condition. A lead level should be considered, not as a cause of microcytic anemia, but because of its association with iron deficiency due to

Children, especially the very young tolerate chronic anemia extremely well. It is not unusual for a toddler with a hemoglobin well below five to act perfectly normal, with the very slow onset of pallor as the only manifestation of the anemia. Some fussiness and irritability might be noticed in retrospect. Often these children appear yellow due to underlying normal pigments. True jaundice can be ruled out if the sclerae are white, and lab evaluation of liver function is therefore not necessary. Hepatosplenomegaly is unusual, as is true decompensation e.g. heart failure, but shortness of breath on exertion and headache are

The therapy of iron deficiency anemia is strongly guided by the cause. Iron therapy is only part of the treatment. For mild anemias due to previous iron loss that has resolved, oral iron is all that is required. If bleeding is ongoing, iron may partially correct the anemia without affecting the underlying cause, leading to delay in diagnosis and therapy of the underlying cause. The most egregious example is the adult with colon cancer; Iron therapy alone would

Transfusions are usually not required, especially in children, but should be considered in cases of decompensation or heart failure. It is said that transfusions for chronic anemia in

underlying cause is entirely outside the marrow.

pica and increased lead absorption, especially in small children.

common in older children and young adults.

**7. Therapy of iron deficiency anemia** 

allow the cancer to progress without diagnosis.

routes should be considered if the history is not consistent with the more common causes or if the patient does not respond adequately to therapy.
