Acute Pancreatitis Induced by Azathioprine and 6-mercaptopurine Proven by Single and Low Dose Challenge Testing in a Child with Crohn Disease
A 14-year-old boy who had been diagnosed with Crohn disease was admitted suffering from high fever and epigastric pain for 5 days. High fever and epigastric pain developed after 34 days of mesalazine and 15 days of azathioprine, after completion of initial treatment with antibiotics and steroid tapering.\nPrior to 40 days before admission, the patient had been admitted suffering from intermittent hematochezia, diarrhea and weight loss for 3 months. Colonoscopy and biopsy had diagnosed Crohn disease. Pediatric Crohn Disease Activity Index score was 57 as moderate/severe degree. The patient had initially been administered antibiotics and steroid, followed by mesalazine (1,500 mg/day) first and later switching this to azathioprine (75 mg/day) only, allowing overlapping period of the two medications before reaching azathioprine-only regimen. No family history of IBD or pancreatitis was identified. Parity was unremarkable. The patient had been born full term with a birth weight of 3,400 g by normal vaginal delivery.\nThe patient's vital sign was 110/60 mmHg of blood pressure, 98/min of heart rate, 20/min of respiratory rate, and body temperature of 39.1℃. The patient showed mild dehydration, soft and non-distended abdomen, and there was no hepatosplenomegaly. Epigastric and periumbilical area tenderness were evident, but no rebound tenderness. Hemoglobin was 11.1 g/dL, hematocrit was 31.5%, white blood cell count was 11,660/mm3 (neutrophil 86%, lymphocyte 8%), platelet was 312,000/mm3. Serum sodium was 138 mEq/L, potassium 3.6 mEq/L, aspartate aminotransferase/alanine aminotransferase 15/7 U/L, total/direct bilirubin 0.9/0.3 mg/dL, calcium 8.6 mg/dL, and phosphorus 3.3 mg/dL. Erythrocyte sedimentation rate was elevated to 54/26 mm/hr, C-reactive protein to 13.32 mg/dL, and amylase and lipase to 227 U/L (normal range, 0-220) and 363 U/L (normal range, 3-110). Anti-nuclear antibody, lupus anticoagulant antibody, rheumatoid factor, anti-smooth antibody, anti-microsomal antibody, antineutrophil cytoplasmic autoantibodies profile were all negative, and serum IgG was 813.96 mg/dL (normal range, 800-1,700). Abdominal ultrasonography showed mild swelling of the pancreas with no demonstrable pancreatic fluid collection.\nThe patient was diagnosed with acute pancreatitis and received supportive care, but the fever and abdominal pain continued. Two days later after admission, amylase and lipase was more elevated as 1,080 U/L and 1,912 U/L, abdominal ultrasonography showed aggravated pancreatitis with marked swelling. Drug-induced pancreatitis was presumed, and mesalazine and azathioprine were discontinued. The patient was fasted and was given total parenteral nutrition. Two days later after drug discontinuance, the fever and epigastric pain subsided, and 4 days after drug discontinuance, amylase and lipase had decreased (93 U/L and 150 U/L, respectively).\nAt that time, the biological medication for Crohn disease in children was not included in the approved lists of Korean Medical Insurance. Therefore, we had to confirm exactly the relationship between prescribed medications and pancreatitis. When we had a plan ahead of a medication challenge test, we were also afraid of serious adverse reaction of pancreatitis in an ethical aspect for the patient. However, the benefits from the challenge test thought to be overweight the possible risks in the aspect of deciding the patient's present and future treatment regimen.\nTherefore, single and low dose challenge tests were performed to confirm the relationship of drug adverse drug reactions and acute pancreatitis (). Before the challenge tests, amylase and lipase values were 132 U/L and 110 U/L, respectively. Two hours after a single administration of azathioprine (50 mg), the patient developed epigastric pain without vomiting. Seven hours after the single administration, the symptom had subsided. Six hours after the challenge test, amylase and lipase values were markedly increased (303 U/L and 443 U/L, respectively) and were further elevated (458 U/L and 909 U/L, respectively) 18 hours later. Three days following the challenge test, the amylase and lipase values had normalized. One day later, the challenge test was repeated with a single administration of 6-mercaptopurine (25 mg) to select an alternative drug. Before the challenge test, amylase and lipase values were 114 U/L and 83 U/L, respectively. Six hours later, the patient developed epigastric pain without vomiting. The symptom had subsided 12 hours later. Six hours later from the challenge test, the amylase and lipase values were increased (155 U/L and 156 U/L, respectively). Eighteen hours later, the amylase and lipase values were further increased (161 U/L and 193 U/L, respectively). Two days from the challenge test, the amylase and lipase values had normalized.\nAfter 1-month steroid maintenance therapy, the mesalazine challenge test was done. The challenge test with a single administration of mesalazine (500 mg) did not elicit vomiting or epigastric pain. Before the test, amylase and lipase values were 139 U/L and 48 U/L, respectively. Twelve hours later, the amylase and lipase values were 114 U/L and 41 U/L, respectively, and were 110 U/L and 39 U/L, respectively, 18 hours later. This was interpreted as a negative response.\nThe patient was administered solely with mesalazine. Despite regular medication for 1 year, Crohn disease relapsed as intermittent perianal abscess and diarrhea with hematochezia. Symptoms subsided after administration of infliximab. Presently, the patient is symptom-free and is being followed-up on an outpatient basis.