CHRISTINA L. MASTER
HISTORY OF PRESENT ILLNESS
The patient is a 5-year-old girl with a recent diagnosis of cystic fibrosis who presents with several weeks of watery stools. She has been treated with pancreatic enzyme supplements for pancreatic insufficiency associated with cystic fibrosis. Increasing the pancreatic enzyme supplementation did not alter her stooling pattern. There was also no improvement of her diarrhea while on a clear liquid diet. She was started on metronidazole 2 days prior to admission for possible parasitic infection. Stool tests for ova and parasites, Giardia antigen by enzyme-linked immunosorbent assay, and Clostridium difficile toxins A and B were negative. Her symptoms worsened with increased abdominal distension and lethargy. She has had a 2-kg weight loss during the last 3 weeks. She has no fever or vomiting. She has normal urine output.
The girl was the product of a full-term uncomplicated pregnancy. She did not have meconium ileus at birth. She was diagnosed with cystic fibrosis 9 weeks prior to this admission. She presented at that time with failure to thrive with foamy, foulsmelling stools. Her diagnosis was delayed due to the finding of Dientamoeba fragilis, which was treated with iodoquinol, and Blastocystis hominis, which was treated with metronidazole, 5 months prior to the diagnosis of cystic fibrosis. Despite treatment and follow-up stool tests, which were negative, she did not gain weight, although her diarrhea had transiently resolved until the past several weeks. Her current medications include metronidazole, albuterol, nebulized cromolyn sodium, pancrelipase capsules, and vitamins A, D, E, and K. Her family history is significant for an older sibling who has a history of constipation and poor growth.
T 37°C; RR 32/min; HR 147 bpm; BP 109/68 mmHg
Weight and height are far below the 5th percentile
Physical examination revealed a lean girl with no rhinorrhea, slightly dry mucous membranes. The remainder of her head and neck examination was normal. Her cardiac and respiratory examinations were normal except for mild tachycardia. Her abdomen was protuberant but otherwise unremarkable. Her rectal examination revealed a minimal amount of stool, which was heme negative. Her extremities were wasted with very little subcutaneous fat. There were no skin rashes. Her neurologic examination was nonfocal.
Chest radiograph revealed mildly increased interstitial markings but no focal infiltrates. A complete blood count revealed a WBC count of 13 100 cells/mm3 (40% segmented neutrophils, 46% lymphocytes, 14% monocytes), and a hemoglobin of 12.7 g/dL, and a platelet count of 472 000 cells/mm3. Her erythrocyte sedimentation rate was 5 mm/h. Serum electrolytes, blood urea nitrogen, serum creatinine, and serum glucose were normal. Her serum alanine aminotransferase was mildly elevated at 56 U/L as was her aspartate aminotransferase at 68 U/L. Her serum alkaline phosphatase was low at 72 U/L, as was her serum albumin at 1.9 g/dL, and total protein at 3.8 g/dL.
The girl’s stool pH was 6.0 and her routine stool cultures were negative. Stool examination was negative for ova and parasites and assays for C. difficile toxins A and B were negative. Tests for Giardia lamblia antigen and Cryptosporidium were negative.
COURSE OF ILLNESS
All feeding attempts resulted in abdominal distension and pain. Abdominal radiograph showed the presence of stool, dilated loops of small bowel with air fluid levels. Upper gastrointestinal barium study with small bowel follow through suggested the diagnosis (Figure 17-5).
FIGURE 17-5. Upper gastrointestinal study with small bowel follow-through similar to that of the patient’s. (Reproduced, with permission, from Avery ME, First LR, eds. Pediatric Medicine. Baltimore: Williams & Wilkins; 1989, p. 435.)
DISCUSSION CASE 17-5
In the context of her recent diagnosis of cystic fibrosis, this patient has many symptoms of chronic malabsorption, including poor weight gain, chronic diarrhea, and abdominal distension. Inadequate management of her cystic fibrosis could account for her symptoms, as could infectious causes of chronic diarrhea superimposed on the diagnosis of cystic fibrosis. Clostridium difficile, G. lamblia, and Cryptosporidium are potential culprits. Celiac sprue should be considered in the differential due to reports of an association with cystic fibrosis.
The upper gastrointestinal barium study revealed thickened, dilated small bowel loops with prominent valvulae conniventes resulting from the dilatation (Figure 17-5). This finding suggested the diagnosis of celiac sprue. Duodenal bulb biopsies showed intense lamina propria inflammatory cells with villous blunting and ulceration with almost complete villous flattening and inspissated secretions in some crypts. Antigliadin IgG >140 mg/dL (normal <15 mg/dL), IgA >136 mg/dL (normal <4 mg/dL). Antiendomysial IgA titer was 1:320. The diagnosis is celiac sprue in the setting of cystic fibrosis.
INCIDENCE AND EPIDEMIOLOGY OF CELIAC SPRUE
Celiac disease, also known as celiac sprue or glutensensitive enteropathy, is a multifactorial autoimmune disorder occurring in genetically susceptible persons. The disease results from abnormal immune responses to the enzyme tissue transglutaminase. In the United States, the prevalence has been estimated at 1 per 3000 in the population. However, recent sero-prevalence studies suggest that the prevalence may be as high as 1 in 120 to 1 in 300 persons in Europe and North America. There is an ethnic predisposition in Western Europeans and their descendants. It rarely occurs among people from an African-Caribbean, Chinese, or Japanese background. Girls are slightly more frequently affected than boys. There is a familial predisposition, with approximately 10% of patients with affected first-degree relatives and greater than 95% of patients with celiac sprue express a specific HLA-DQ heterodimer. In a cohort of children with cystic fibrosis from Norway and Sweden, the prevalence of celiac disease of 1.2% (1:83) was found to be approximately threefold higher than the general population of those countries.
Celiac sprue is a malabsorptive condition caused by an autoimmune T-cell-mediated response against gluten that results in severe inflammation in small bowel mucosa. The classic presentation is in infants who develop diarrhea, abdominal distension, and failure to thrive as cereals are introduced into their diet, typically between 6 months and 2 years of age. Vomiting, anorexia, and abdominal pain may be associated. Affected infants may develop iron-deficiency anemia and rickets secondary to the malabsorption. Older children and adolescents may not present with malabsorptive symptoms, but rather with hypertransaminasemia, short stature, pubertal delay, or recurrent aphthous ulcers. Adults may present with a history of symptoms that date back to childhood, or may present with no previous symptoms whatsoever. Diarrhea with lactose-intolerance and steatorrhea are common, as is steatorrhea. Weight loss with flatulence and abdominal distension also occur. Adults may be otherwise asymptomatic and present only with anemia due to iron-deficiency or recurrent aphthous ulcers.
Extraintestinal manifestations may be present without significant gastrointestinal symptoms. Dermatitis herpetiformis, a pruritic papulovesicular rash on the extensor surfaces of the extremities and trunk, is associated with dermal IgA deposits; the lesions resolve with withdrawal of gluten from the diet. Other extraintestinal manifestations include dental enamel hypoplasia, hepatitis, arthritis or arthralgias, seizures (from intracranial calcifications), and other autoimmune conditions, including thyroiditis and type I diabetes mellitus.
Patients with refractory celiac disease are at increased risk for developing enteropathy-associated T cell lymphoma. These patients have severe symptoms despite adherence to a gluten-free diet for at least 6 months. This condition often requires treatment with corticosteroids or immunosuppressants. Strict adherence to a diet free from gluten can decrease the risk of cancers associated with celiac disease.
Endoscopy. Endoscopy with biopsy of the small intestine remains the reference standard for diagnosis. Pathologic specimens reveal the presence of absent or flattened villi with hyperplastic crypts and a significant presence of inflammatory lymphocytes and plasma cells. These findings generally resolve after withdrawal of gluten from the diet, but the resolution of pathologic findings generally lags behind signs of clinical improvement. Currently, repeat biopsies are not necessary due to the highly accurate nature of the available serologic tests.
Serologic tests. Serologic tests have high sensitivity and specificity for the diagnosis of celiac disease. IgA antiendomysial antibodies are reported to be 85%-98% sensitive and 97%-100% specific compared with intestinal biopsy. Antigliadin IgA and IgG are much less specific and have moderate sensitivity and can be seen in adults with nonspecific gastrointestinal inflammation and are not as useful. In children younger than 2 years of age, however, IgA antigliadin is the most useful serologic marker. All of these markers respond to withdrawal of gluten and often become undetectable within 3-6 months after initiation of the appropriate dietary regimen. Serologic tests are currently used to identify children who warrant intestinal biopsy for confirmation of celiac disease.
Radiographic studies. Abdominal radiographs and upper gastrointestinal series using barium are no longer necessary in making the initial diagnosis, given the high sensitivity and specificity of serologic testing combined with endoscopy findings. Radiographic imaging, including computed tomography may be helpful, however, in evaluating patients with refractory celiac disease, especially for signs of intestinal lymphoma.
Tests of malabsorption. Measurement of fecal fat or oral D-xylose absorption are not specific and therefore, not necessary, and merely serve to confirm the malabsorptive nature of the condition.
Gluten withdrawal. Empiric elimination of gluten from the diet is not indicated because the results of intestinal biopsy following this intervention may be equivocal and serologic tests are less reliable when gluten has been eliminated from the diet.
The definitive therapy for celiac disease is lifetime avoidance of gluten in the diet. Complete avoidance is probably impossible due to the widespread presence in processed foods, but elimination of products that contain wheat gluten, barley, or rye is important. Oats should also be avoided initially but may be slowly reintroduced in some patients without serious consequences. Studies have documented the safety of oats for patients with celiac disease. However, cross-contamination is a concern because oats are often harvested and processed in facilities used for preparing wheat-based flours. Dairy products are also initially avoided due to a secondary lactase deficiency and may be reintroduced in the diet a few months later. A multivitamin is also important, in addition to correcting any severe vitamin deficiencies that may be present. Patients with hyposplenism should receive antibiotic prophylaxis for invasive procedures.
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