Exocrine pancreatic insufficiency (EPI) is rare in childhood outside cystic fibrosis (CF). Shwachman's syndrome is the second most common cause of inherited EPI and is associated with pancreatic lipomatosis. The latter is also a feature of the less common Johansen-Blizzard syndrome in which there are morphologic abnormalities. Even rarer is EPI due to pancreatic fibrosis which, associated with marrow failure, is a feature of Pearson's syndrome. Single-enzyme deficiencies of the pancreas are also described (1). Coeliac disease (CD) characteristically begins in childhood. Although the pathophysiology of CD is not fully understood, there is no known causal association with EPI. A transient form of EPI has been documented in some newly diagnosed patients with coeliac disease, however, resolving with a gluten-free diet (1). Although these patients have a diminished secretion of pancreatic bicarbonate and enzymes in response to a meal or duodenal acidification, intravenous secretin produces normal pancreatic secretion indicating that the pancreas is not diseased (2). An increased incidence of CD has been reported in the CF population although an association is disputed (3). In adults, apart from transient EPI, severe irreversible pancreatic insufficiency has been reported in elderly patients with long-standing CD (4), and pancreatic atrophy and fibrosis have been documented in postmortem studies of patients with CD (5). Pancreatic failure due to pancreatic atrophy and fibrosis was also discovered in a 17-year-old boy who failed to respond to treatment for CD (6). Apart from the young age, this case appears to be similar to reports in elderly patients. We describe a case of EPI in an infant with steatorrhea from the first weeks of life, in whom CD was diagnosed at 18 months of age.
An 18-month-old girl was referred to our hospital with a 5-month history of passing soft poorly formed stools, distended abdomen, weight loss, lethargy, and irritability. However, from the first few weeks of life her mother had noticed oil separating from the stool on her diaper. She was admitted to the referring hospital at 3 weeks of age for failure to gain weight, abdominal distension, and abnormal stools for which no cause had been found. At 18 months, clinical examination showed her to be marasmic with wasting, marked abdominal distension, and visible peristaltic bowel loops (Fig. 1). Initial investigations showed positive organ-specific IgA antibodies to gliadin, endomysium, and reticulin. Findings in a small bowel biopsy were consistent with CD showing partial villous atrophy, crypt hyperplasia, an increase in intraepithelial lymphocytes, and focal inflammation of the lamina propria.
Treatment with a gluten-free diet resulted in an improvement in the consistency of stools, weight gain, normal behavior and a reduction in abdominal distension. However, during follow-up visits, the mother remained concerned. Although there was symptomatic improvement and an increase in height and weight velocity, intermittent symptoms, similar to those seen soon after birth, persisted and were largely unchanged by treatment.
Almost a year after the patient began consuming a gluten-free diet, antibodies to gliadin and endomysium were still weakly positive, although there were no concerns regarding dietary compliance. In view of the history a 3-day faecal fat collection was performed confirming steatorrhea (26 g/day), and stool chymotrypsin was undetectable. Pancreatic supplements were therefore administered and titrated to produce normal stools.
Eighteen months later, her symptoms had gone, and growth had improved dramatically. Weight had gone from the 3rd percentile at diagnosis of CD to the 25th percentile after the patient began a gluten-free diet (Fig. 2) and the 90th percentile after introduction of pancreatic supplements. In the same period height had gone from the 25th percentile to the 50th percentile after the inception of the diet and to the 90th percentile after supplements (midparental height, 90th percentile).
A review when the patient was aged 4.5 years revealed no significant infective illnesses at any stage. There was no evidence of neutropenia or thrombocytopenia on numerous blood counts over the years, and a sweat chloride test performed on two occasions had yielded negative results. Organ-specific antibodies had taken 2 years to disappear from the beginning of the gluten-free diet.
Further investigations including long bone, chest, and abdominal radiographs; plasma immunoglobulins; IgE radioallergosorbent test for allergy to cow's milk and eggs; and autoantibody screen produced normal results. Ultrasonography revealed a normal-sized pancreas with increased echogenicity compatible with lipomatosis. Human leucocyte antigen (HLA) analysis showed associations with B8, DR3, and DQ2. A specimen obtained in a second small bowel biopsy showed normal histology, and severe EPI was confirmed by exocrine pancreatic function tests (Table 1) performed adapting an established method (7).
The symptoms in this case are strongly suggestive of pancreatic insufficiency in the neonatal period, and abnormal pancreatic function test results 4 years later confirmed EPI. The picture of crypt hyperplasia, intraepithelial lymphocytes, and an inflammatory infiltrate of the lamina propria are characteristic of CD, although total rather than partial villous atrophy is the usual histologic finding (1). Immunologic data in association with the clinical evidence and HLA markers, rule out other possible diagnoses. The association of congenital EPI with CD has not been reported previously.
In adults, EPI has been documented in a few, mainly elderly, patients with CD (4). The initial symptoms in most are similar to those in our case-that is, difficulty in treating symptoms of CD with appropriate diet prompted further investigation and subsequent discovery of EPI. Pancreatic atrophy and fibrosis in these patients with poorly controlled, long-standing coeliac disease is postulated to be a consequence of chronic understimulation of the pancreas by secretagogues (6). Protein calorie malnutrition is also known to cause EPI with acinar atrophy and eventual pancreatic fibrosis (4,5). In our case apart from both conditions appearing in infancy, EPI in the neonatal period clearly predates the onset of CD, and therefore the above mechanism cannot apply. As stated, there is no evidence to suggest EPI could have a causal role in the pathophysiology of CD. When CD has been reported in the CF population, it has been suggested that an abnormal intestinal antigen load due to pancreatic malabsorption may act as a trigger in those with potential coeliac disease who would not otherwise have sought medical attention at the time (3). However, the characteristic finding on small bowel biopsy in CF is quite unlike that of CD and includes the presence of inspissated mucus in the small bowel mucosa (9).
Because sweat chloride was at a normal level in our case, the findings of severe pancreatic insufficiency (Table 1) with symptoms dating from birth are consistent with primary hypoplasia of the pancreas (1). Shwachman's syndrome is the most common cause of pancreatic hypoplasia, but there were no associated features in our case to suggest this or any of the other syndromes mentioned earlier. Pancreatic histology may provide a definitive diagnosis but is not an option in these circumstances.
Because this is the first case of its kind, without a cause for the EPI the natural history and prognosis are difficult to predict. In the reported adult cases, CD seems to be well controlled with an appropriate diet, and EPI although adequately treated with supplements is lifelong in view of pancreatic fibrosis. Congenital EPI, however, may have a different outcome. In some cases of Shwachman's syndrome an improvement has been seen in the degree of clinical EPI after early childhood (1,10).
It is known that some patients with CF, despite significant EPI on testing, may have few if any symptoms of pancreatic malabsorption, similar to some patients with Shwachman's syndrome (10). Under these circumstances, CD may unmask this subclinical state. In the case reported here the severity of EPI in the neonatal period pre-empted any effect from CD. Magnetic resonance imaging performed at a later date may further clarify the diagnosis (11), and a gluten challenge should be performed to prove CD beyond any doubt.
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