**4.2.1 Discussion**

This child presents with a common cause of iron deficiency anemia in the 1-2 year old. Just as in the adult male in the first case above, he has an *acquired*, *severe* anemia that is *severely* microcytic, and by far the most likely cause is chronic gastrointestinal blood loss. And like the adult, this child requires a GI workup. However, in this case an adequate workup consists mostly of the history of excess milk consumption along with the physical exam and some simple labs to classify the severity and type of anemia, so no referral to a pediatric gastroenterologist is required, and endoscopic procedures are not needed. If the history of excessive milk consumption were not present, then such a referral would be required, and procedures such as a Meckel's scan or endoscopy would be needed to find another cause, i.e. a specific gastrointestinal lesion.

Consumption of cow's milk may contribute to iron deficiency through several mechanisms. Whole milk given to young infants under a year of age, especially under 6 months of age, leads to iron deficiency anemia (American Academy of Pediatrics, 1992; Chessare, 1988; Fomon et al., 1981; Tunnessen & Oski, 1987; Wilson et al., 1964). Cow's milk and human milk both have low iron content, but the bioavailability of iron in human milk is greater. (Picciano & Deering, 1980) Cow's milk also replaces iron-rich foods in the diet. In addition, components in cow's milk such as calcium and caseinophosphopeptide can directly interfere with iron absorption (Ani-Kibangou et al., 2005; Hallberg et al., 1992). For severe anemia, these mechanisms can exacerbate the anemia, along with increased demand from the neonatal growth spurt, but the major mechanism is direct gastrointestinal bleeding.

Whole milk protein causes an enteropathy in the immature gut that leads to GI bleeding. What is not generally understood however is that these same effects continue into the 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 moderate amounts with meals.

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

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

256 New Advances in the Basic and Clinical Gastroenterology

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

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

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

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

This child presents with a common cause of iron deficiency anemia in the 1-2 year old. Just as in the adult male in the first case above, he has an *acquired*, *severe* anemia that is *severely* microcytic, and by far the most likely cause is chronic gastrointestinal blood loss. And like the adult, this child requires a GI workup. However, in this case an adequate workup consists mostly of the history of excess milk consumption along with the physical exam and some simple labs to classify the severity and type of anemia, so no referral to a pediatric gastroenterologist is required, and endoscopic procedures are not needed. If the history of excessive milk consumption were not present, then such a referral would be required, and procedures such as a Meckel's scan or endoscopy would be needed to find another cause,

Consumption of cow's milk may contribute to iron deficiency through several mechanisms. Whole milk given to young infants under a year of age, especially under 6 months of age, leads to iron deficiency anemia (American Academy of Pediatrics, 1992; Chessare, 1988; Fomon et al., 1981; Tunnessen & Oski, 1987; Wilson et al., 1964). Cow's milk and human milk both have low iron content, but the bioavailability of iron in human milk is greater. (Picciano & Deering, 1980) Cow's milk also replaces iron-rich foods in the diet. In addition, components in cow's milk such as calcium and caseinophosphopeptide can directly interfere with iron absorption (Ani-Kibangou et al., 2005; Hallberg et al., 1992). For severe anemia, these mechanisms can exacerbate the anemia, along with increased demand from the

neonatal growth spurt, but the major mechanism is direct gastrointestinal bleeding.

Whole milk protein causes an enteropathy in the immature gut that leads to GI bleeding. What is not generally understood however is that these same effects continue into the

back to the diet, but only with meals, as soon as the anemia had begun to improve.

hepatosplenomegaly. His extremities were well perfused with no edema.

significant family history.

only 4 mcg/dL.

**4.2.1 Discussion** 

i.e. a specific gastrointestinal lesion.

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

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 mg PO daily started a week prior.

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

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 perfused, and his neurologic exam was grossly intact.

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 electrophoresis was normal and his blood smear was normal.

A Case Based Approach to Severe Microcytic Anemia in Children 259

found to be profoundly anemic with a hemoglobin of 5.9 g/dL, MCV 68.2 fL with symptoms of anemia requiring several blood transfusions. She was started on oral birth control pills

Apart from dysfunctional uterine bleeding, the patient did not have a past medical history of bleeding problems, nosebleeds, easy bruising, petechiae or mucosal bleeding. She denied any loose, bloody, tarry stools or abdominal pain. She had no food allergies. She was healthy before the onset of menarche except for daily headaches which had been evaluated by CT. Her father said he experienced similar headaches as an adolescent. Her father denied a family history of bleeding disorders or menorrhagia. She was doing well in 7th grade and

In clinic the patient was alert and in no apparent distress. She was afebrile, with normal vital signs. Skin was unremarkable with no petechiae or bruising. Her conjunctivae were pink without pallor. Abdomen was soft, nontender, nondistended without hepatosplenomegaly. A comprehensive coagulation workup showed no evidence of a systemic bleeding disorder. At the time of her visit to pediatric hematology clinic her hemoglobin was 12.5 g/dL, MCV

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

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

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

with resolution of her menorrhagia. She was also started on daily iron sulfate tablets.

enjoyed cheerleading.

**5.1.1 Discussion** 

anemia, as in this case.

82.4, fL, both normal. A ferritin level was normal.

heavy periods, a gastrointestinal cause should still be sought.

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 in alleviating his symptoms and his anemia.
