Page 2492 - Hematology_ Basic Principles and Practice ( PDFDrive )

2224 Part XIII Consultative Hematology

paper that also demonstrated a correlation between the amount of supplementation, and a significant percentage of children and adults
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milk ingested and the amount of fecal blood lost. GI blood loss in with iron-deficiency anemia who do not respond to therapeutic oral
response to cow’s milk ingestion appears to be most prevalent in iron replacement have celiac disease.
infants younger than 6 months of age and occurs with diminishing Folic acid and, with a lesser frequency, vitamin B 12 deficiency may
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frequency in older infants. The majority of affected infants outgrow also result from the malabsorptive process in celiac disease. Manifesta-
their milk protein sensitivity by 3 years of age. The GI blood loss may tions may include macrocytic anemia, leukocytopenia, and pancyto-
be ameliorated by heat denaturing of the milk proteins. Occasionally, penia. Neurologic findings may be present with vitamin B 12 deficiency.
toddlers and older children have been documented to have milk- Other vitamin and micronutrient deficiencies, including copper and
induced GI bleeding with associated iron-deficiency anemia. 193,194 vitamin K deficiency, have been observed in celiac disease. Splenic
Substantially limiting cow’s milk consumption and prescribing iron hypofunction may occur with some frequency in adults with celiac
supplementation are sufficient to correct the iron deficiency and disease but appears to be less common in children. A number of case
associated hypoproteinemia with edema in most children. 195 reports have suggested an association of pulmonary hemosiderosis
A variety of GI syndromes associated with cow’s milk sensitivity, with celiac disease. 207,208 The pathophysiology of this association is
with varying manifestations and severity, have been described. Associ- not known, but the pulmonary process may improve with initiation
ated findings may include vomiting, diarrhea, poor growth, and of a gluten-free diet.
hypoproteinemia; however, some patients may have occult blood loss A high index of suspicion is important for diagnosing celiac
and iron-deficiency anemia without associated complaints. At the disease in children, particularly those who are minimally symptomatic
severe end of the spectrum, cow’s milk protein–induced enterocolitis or who may be at increased risk for development of celiac disease.
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may occur. Such patients may present with acute, severe bloody The latter group includes children with trisomy 21, Turner syndrome,
diarrhea; vomiting; abdominal distention; methemoglobinemia; and IgA deficiency, autoimmune thyroiditis, and type 1 diabetes mellitus,
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shock even in the absence of anemia. Even minute amounts of cow’s as well as those with a family history of celiac disease. In addition to
milk protein in human breast milk may be sufficient to precipitate a correcting the nutritional deficiencies and growth failure in children
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severe event. In patients with chronic occult GI blood loss, esopha- with celiac disease, recognition of the disease and institution of a
gogastroduodenoscopy may reveal gastritis or gastroduodenitis, and gluten-free diet may minimize the risk of some of the associated
colonoscopy may demonstrate modest histologic abnormalities in the conditions of celiac disease, including the development of non-
proximal colon. 194,198 The immunopathobiology of cow’s milk protein Hodgkin lymphoma involving the intestinal tract.
allergy syndromes has not been fully elucidated. Most of these syn-
dromes affecting the intestinal tract only are non–IgE mediated. 199,200
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Wilson et al reported the frequent presence of precipitating anti- Inflammatory Bowel Disease
bodies to milk proteins in their study population as a whole. However,
the presence of such antibodies did not appear to predict milk-induced Anemia is a very common extraintestinal manifestation of inflamma-
GI bleeding. The roles that genetic predisposition, intestinal and tory bowel disease (IBD), particularly in children with Crohn disease,
immunologic immaturity in young infants, exposure to cow’s milk in whom the historical prevalence of anemia approaches 70% to
protein in breast milk, GI infections, or other factors may play in the 80%. 209,210 A more recent series of studies suggests that the prevalence
development of milk protein enteropathy are not fully understood. of anemia may be declining in Crohn disease, perhaps because of
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In 1962, Heiner et al described a syndrome in infants and young more effective therapy. The etiology of anemia in IBD appears to
children that included chronic cough, recurrent lung infiltrates, poor be multifactorial, but the most common contributing factors are iron
growth, GI symptoms, blood loss, iron-deficiency anemia, and pul- deficiency related to chronic GI blood loss or iron malabsorption
monary hemosiderosis associated with multiple serum precipitins to caused by intestinal mucosal injury and decreased absorption and
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cow’s milk proteins. Others have confirmed and further detailed sequestration of iron stores as is seen in the anemia of chronic inflam-
this rare syndrome. 201–203 Additional manifestations may include mation. These broad mechanisms for anemia may coexist, and it is
intermittent wheezing; hilar lymphadenopathy; eosinophilia; elevated sometimes difficult to determine the predominant mechanism.
levels of serum IgE, IgM, or IgA; chronic rhinitis; adenoidal hyper- Measurement of serum soluble transferrin receptor and the hemoglo-
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trophy; hypercapnia; and cor pulmonale. A feature of this syndrome bin content of reticulocytes can be helpful in this setting. Other
is rapid improvement of the pulmonary manifestations after eliminat- factors contributing to anemia in IBD may also be present in indi-
ing cow’s milk from the diet. vidual patients, including immune-mediated hemolytic anemia,
hemophagocytosis, malnutrition, folate and vitamin B 12 deficiency,
and the suppressive effects of medications on hematopoiesis. 213
Celiac Disease Specific treatment of anemia in IBD may be difficult. Oral iron
supplementation is not always effective. Comparative studies of oral
Celiac disease, or gluten-sensitive enteropathy, is an inflammatory versus intravenous iron supplementation suggest the intravenous
and malabsorptive process resulting from an aberrant intestinal T-cell route may result in better short-term improvement in anemia;
immune response to ingested dietary gluten, leading to injury of the however, long-term outcome data are lacking. 214,215 Some patients
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mucosa of the small intestine. Classical celiac disease has been may respond to supplemental erythropoietin administration as
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characterized as frequently affecting infants and young children, well. Patients with IBD may have impaired enterocyte-mediated
leading to steatorrhea, failure to thrive, weight loss, and nutritional intestinal absorption of iron, the degree of which appears to correlate
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deficiency. With the advent of improved screening techniques, the with disease activity. The role that induction of hepcidin expression
prevalence is recognized to be greater than previous estimates. Celiac by mediators of inflammation, particularly IL-6, plays in the anemia
disease broadly affects both children and adults, many of whom may of IBD is an intriguing area of ongoing investigation. 217,218
have minimal classical symptoms of the disorder. Treatment is usually Other hematologic manifestations of IBD include leukocytosis
institution of a gluten-free diet, with resolution of the process in the and thrombocytosis, hyposplenism, an increased propensity toward
majority of cases. thrombosis, and therapy-related leukopenia and thrombocytopenia.
Iron deficiency is frequently present in celiac disease in children There may be an increased incidence of immune-mediated thrombo-
and adults and may be the sole recognized manifestation of the dis- cytopenia associated with IBD. 219
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order. Dietary iron absorption occurs primarily within the proximal
small intestine, the same region most affected by celiac disease. As a
result, iron deficiency in celiac disease appears to be caused primarily Other Gastrointestinal Disorders
by impaired absorption of dietary iron, although a component of
chronic GI blood loss may also apply in a minority of patients. 205,206 In addition to the disorders already discussed, other GI disorders
Iron deficiency in celiac disease may be refractory to iron that occur in children and adolescents may be associated with the