The typical morphologic changes within the pancreas of patients with cystic fibrosis are inter- and intralobular fibrosis and destruction of the pancreatic parenchyma. The small ducts become obstructed by secretions and cellular debris, leading to formation of microcysts. Eventually, the pancreas becomes shrunken and fibrosed, with fatty infiltration of the parenchyma(1-3). On rare occasions, it contains epithelia-lined macrocysts and calcification (4). The pancreatic changes in cystic fibrosis rarely cause abdominal pain except in small numbers of patients who suffer acute pancreatitis. In most of these cases, patients have sufficient pancreatic function(5,6). We report a child with pancreatic insufficiency with cystic fibrosis, in whom severe gastrointestinal symptoms developed, associated with a previously undescribed complication of the pancreas.
Our patient, a 5-month-old boy, had a history of recurrent chest infections and failure to thrive. Results of repeated microscopic examination of the stool were positive for fat globules, confirming a clinical suspicion of steatorrhoea caused by pancreatic insufficiency. A diagnosis of cystic fibrosis was confirmed by two sweat tests, using pilocarpine iontophoresis(sweat sodium, 112 mmol/l and 109 mmol/l in 108 mg and 237 mg sweat, respectively). Genetic testing showed him to be heterozygous for theΔF508 and the S489X cystic fibrosis mutations. Therapy was begun with pancreatic enzyme supplements, an energy-dense diet, and regular chest physiotherapy, which resulted in improved growth. He thrived normally during the next few years.
At 6 years of age, he started to complain of intermittent pain and swelling in his large joints, particularly in his knees. He was treated with nonsteroidal antiinflammatory drugs on an infrequent basis (200 mg ibuprofen, as required). Results of a full autoimmune profile were negative, blood counts were normal, and erythrocyte sedimentation rate (ESR) measured 28 mm/hr.
When he was seven years old, symptoms of polyuria, polydipsia, weight loss, and hyperglycaemia developed. A diagnosis of diabetes mellitus was confirmed, and he began receiving subcutaneous insulin injections twice daily. A dose of 0.5 U/kg per day maintained control of his blood sugar levels. Results of tests for islet cell antibodies were negative.
During this period, he developed moderately severe lung disease after colonisation with Pseudomonas aeruginosa. He required several hospital admissions for intravenous antibiotic treatment.
At nine years of age, he complained of central abdominal pain radiating to the back and waking him from sleep. His treatment consisted of pancreatic supplements (pancreatin, Creon 25000, Solvay Healthcare Ltd.) at a dose of 22,000 U/kg per day of lipase, inhaled corticosteroids and bronchodilators, inhaled colomycin, vitamin supplements, and insulin. He was still taking nonsteroidal antiinflammatory drugs on an infrequent basis. Serial abdominal ultrasound measurements demonstrated a diffusely enlarged pancreas of high echogenicity. (Fig. 1). The appearances were consistent with a diagnosis of acute pancreatitis, but that was thought to be unlikely. Serum amylase levels were consistently within normal limits. Measurement of full blood count, ESR, C-reactive protein, and liver function yielded normal results (alanine aminotransferase, 20 IU/l; γ-glutamyl transpeptidase, 11 IU/l; prothrombin time, 1.1; partial thromboplastin time, 1.12).
Abdominal ultrasound showed no evidence of abnormal colonic wall thickening, and results of colonoscopic exploration extending to the caecum were entirely normal. Results of a barium contrast study showed a widened duodenal loop around the enlarged pancreas, with normal appearance of the small bowel, and normal barium transit times. A gastroscopic study with biopsy resulted in normal macroscopic and histologic findings in the oesophagus, stomach, and duodenum. Endoscopically obtained specimens were negative forHelicobacter pylori. In an endoscopic retrograde cholangiopancreatogram (ERCP), normal intra- and extrahepatic ducts were observed. In particular, there was no extrinsic compression of the common bile duct. Attempted cannulation of the pancreatic duct was unsuccessful.
Computed tomographic (CT) imaging of the pancreas confirmed a diffusely enlarged pancreas with a lobular outline. It was of markedly low attenuation, consistent with fatty infiltration (Fig. 2). There were also areas of linear and punctate high attenuation within the body of the pancreas, suggesting parenchymal calcification. There was no evidence of macroscopic cystic change.
Despite continued severe gastrointestinal symptoms, weight gain remained satisfactory, with growth remaining within the 25th percentile. His condition was complicated at 10 years of age by loss of glycaemic control. Despite careful supervision of his insulin therapy, he had recurrent hypoglycaemic seizures, requiring multiple hospital admissions.
Abdominal pain continued, causing prolonged school absences. He was unable to participate in physical activities, and symptoms did not improve after treatments with paracetamol, codeine, pethidine, and periods of bowel rest. Further pancreatic enlargement was seen in repeated ultrasound scans. Two months after the initial occurrence of seizures, his pancreas became readily palpable in the center of his abdomen. The mass was tender, lobular in texture, and causing abdominal distension. He was now in continuous pain and requiring inpatient care. Tests of liver function, serum amylase, and acute-phase proteins continued to produce normal results.
In the absence of any other identifiable cause for his symptoms, it was decided to proceed to laparotomy. At operation, a swollen, lobulated pancreas was identified, with no other disease. It was therefore decided to undertake total pancreatectomy, necessitating cholecystectomy and jejunoduodenostomy.
The resected pancreas measured 25 cm × 8 cm × 5 cm and weighed 342 g. (Fig. 3), approximately six times the size of a normal pancreas in a child of this age. There were no macroscopic cysts. Histologic study yielded findings of marked acinar destruction, with extensive microcystic change of interlobular and intralobular ducts. The microcysts were filled with inspissated eosinophilic secretions (Fig. 4), and occasional clusters of chronic inflammatory cells and calcium deposition were evident within the pancreatic connective tissue (not shown inFig. 4). There was no evidence for an infective process. The pancreatic duct appeared normal. The mucosa of the gallbladder was atrophic, and the cystic duct was normal.
The patient made an excellent postoperative recovery. His abdominal symptoms resolved, and he has had no further hypoglycaemic seizures. Seven months after surgery, he had mild gastric symptoms. Gastroscopic examination revealed a friable duodenal mucosa, and non-specific duodenitis was confirmed in histologic studies. The symptoms have resolved completely with cisapride and omeprazole, and discontinuation of nonsteroidal antiinflammatory drugs. He is now 18 months past surgery. Growth has progressed normally within the 25th percentile, and he has remained free of abdominal pain.
A spectrum of morphologic changes within the pancreas of patients with cystic fibrosis has been described (1,2). Typically these changes are those of fatty infiltration of the parenchyma and fibrotic shrinkage. Occasionally, macroscopic cysts of variable size and number are formed (7-9). In rare cases, the pancreas may be completely replaced by multiple macroscopic cysts (pancreatic cystosis)(10). Such changes are typically discovered as incidental findings during routine abdominal ultrasound examination. These cystic changes have never been reported to cause gastrointestinal symptoms.
Abdominal pain in childhood cystic fibrosis can be caused by a variety of disorders including faecal impaction, distal intestinal obstruction syndrome, intussusception, abdominal cramps, and flatulence caused by maldigestion. More recently, fibrosing colonopathy has been described as an important cause of gastrointestinal symptoms and has been associated with high doses of pancreatic enzymes (11-13). Our patient had been receiving a dose of high-strength pancreatin more than double the maximum dosage recently recommended by the Committee on Safety of Medicines(14). His colon has since been studied by ultrasound and found to be of normal thickness. None of the patients with fibrosing colonopathy requiring laparotomy have had similar pancreatic changes described.
Abdominal pain is rarely of pancreatic origin. Approximately 85% of patients with cystic fibrosis have almost complete loss of pancreatic function. It is within the remaining 15%, in whom pancreatic function is sufficient, that the development of acute pancreatitis has been described(15-17). These patients tend to have hyperconcentration of pancreatic secretions, resulting in recurrent episodes of autodigestion of the pancreas by activated proteolytic enzymes. Pancreatitis is thought to be extremely rare in patients with pancreatic insufficiency because they do not have the proteolytic enzymes necessary to promote autodigestion and may not have sufficient viable pancreatic tissue for inflammation to develop. Pancreatic ultrasound appearances in our patient suggested acute pancreatitis, but serum amylase levels were never elevated. It could be postulated that in the context of severe pancreatic destruction, acute pancreatitis could occur with a normal amylase reading, but the histologic examination of the resected organ showed very little inflammatory change.
It is interesting to note that our patient demonstrated early pancreatic endocrine dysfunction, requiring insulin from 7 years of age. It could be postulated that the unusual histologic findings of severe generalised loss of pancreatic tissue were, in part, responsible for early development of endocrine insufficiency, but it is also possible that coincidental classic juvenile diabetes developed. The poor diabetic control during the course of his illness might have been provoked by unusual stress responses to pain and distress.
The diffuse pancreatic enlargement that occurred in our patient has not been previously described in cystic fibrosis. Our patient had an unusual cystic fibrosis mutation, S489X; but this has not been identified as causing an atypical phenotype. His medication was similar to that routinely used in our service. He had received substantial doses of ibuprofen to control his pain. This drug has been used in a 4-year period to treat the lung complications of cystic fibrosis with no reports of pancreatic side effects(18). An extensive review of the literature has not identified ibuprofen as causing abnormalities of pancreatic architecture.
Although there was no evidence of an acute inflammatory process within the resected pancreas, the prompt resolution of pain after surgery suggests that the pancreas had been responsible for abdominal symptoms. The pathophysiology of a causal relation is difficult to determine but might have been related to a mass effect of the pancreatic bulk on adjacent viscera. There was no evidence that enlargement of the head of the pancreas was obstructing the common bile duct.
Although obviously a rare occurrence, this complication should be considered as a possible cause of recurrent severe abdominal pain in cystic fibrosis. The atypical pancreatic swelling is readily demonstrated in examination by ultrasound. Although pancreatectomy is a major surgical undertaking, we believe that the severity of symptoms in this case and their temporal relationship to pancreatic enlargement was sufficient to justify the operation.
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