Perforated duodenal ulcer: a rare complication of deferasirox in children.

Duodenal ulcer perforation in pediatric age group is an uncommon entity; hence, it is not usually considered in the differential diagnosis of acute abdomen in these patients. It is important for the emergency physician to consider perforated peptic ulcer in the differential diagnosis of children presenting with acute abdominal pain, gastrointestinal bleeding, or shock. We report a 6½-year-old male child with thalassemia major who presented to emergency room with an acute abdomen and shock, who was subsequently found to have a perforated duodenal ulcer, probably related to use of oral chelating agent, deferasirox. Although, gastrointestinal symptoms like nausea, vomiting, and abdominal pain has been mentioned as infrequent adverse event in the scientific product information of deferasirox, in our current knowledge this is the first case report of perforated duodenal ulcer after oral deferasirox. The severity of this event justifies the reporting of this case. This patient had an atypical presentation in that there were no signs or symptoms of peptic ulcer disease before perforation and shock he was successfully managed with open surgery after initial resuscitation and stabilization of his general condition.

Introduction

Duodenal ulcer is an uncommonly diagnosed entity in children with an incidence of 1.55 cases/year.[1] Because of its rarity, its diagnosis is usually over-looked unless it presents with complications. The usual manifestations of a complicated duodenal ulcer are perforation and hemorrhage. Even in such cases which present as acute abdomen, it is not considered as a possible diagnosis because of low index of suspicion. The majority of children with active gastritis and ulcers of the stomach or duodenum have an associated systemic condition, such as over-whelming sepsis, severe head or body trauma, or burns.[2] A history of taking medications such as corticosteroids or non-steroidal anti-inflammatory drugs is also important. However, in the absence of such significant history, symptoms of childhood peptic ulcer disease can easily be overlooked in the initial stages, which can result in catastrophic consequences such as perforation or hemorrhage.[34] Oral iron chelator deferasirox became available in the market since 2006 and longer term studies have confirmed efficacy and safety of its use. Gastro-intestinal complaints (mainly vomiting and diarrhea) are reported in phase II trials in pediatric patients with beta-thalassemia major receiving deferasirox.[5] We report a case of perforated duodenal ulcer with oral deferasirox in a 6½-year-old boy with beta thalassemia major.

Case Report

A 6½-year-old Kuwaiti boy presented to emergency room with 3 day history of poor appetite, abdominal pain, vomiting, and fever. On arrival the child was in shock with following vital signs : Heart rate, 170 beats/min; respiratory rate, 60 breaths/min; unrecordable blood pressure and core temperature, 38.5°C. Physical examination revealed cool extremities, weak femoral pulses, and poor capillary refill. The abdomen was distended, tender, and demonstrated guarding with rebound tenderness. Bowel sounds were absent in all quadrants. His chest examination revealed regular heart rate without murmur and clear lungs.

The past medical history revealed that he was born to consanguineous parents who were carriers of thalessemia gene. At 4 months of age he was diagnosed as beta-thalessemia major and was managed by the pediatric hematologist with hpertransfusion therapy. He was under surveillance for iron over load and was put on oral deferasirox (625 mg daily) since past 3 year. He was not on any other medication and never had any gastrointestinal symptoms prior to this illness.

Significant blood investigations included hemoglobin, 103 g/L; urea,12.5 mmol/L; creatinine, 231 mmol/L; CO2, 13 mmol/L; sodium, 126 mmols/L; calcium, 1.80 mmol/L; phosphorous, 2.18 mmols/L; alaninine aminotransferase (ALT), 76 U/L; aspartate aminotransferase (AST), 118 U/L; albumin, 23.5 g/L; Ph, 7.22: HCO3. 17.8 mmol/L with base excess of – 7.8.

Resuscitation was started with intravenous fluids and urgent bed-side plain radiographs were taken which showed free intra-peritoneal air. Pre-operative diagnosis of perforated viscous was made and emergency laparotomy was performed after stabilizing the general condition after three IV bolus (20 mL/kg each) of crystalloids and dopamine infusion (5 ug/kg/h). On entering the peritoneal cavity, a large amount of bile stained fluid was encountered which was evacuated. A discrete perforation of 5 mm × 6 mm size was found on the anterior wall of fist part of duodenum. Simple closure with omental patch followed by peritoneal lavage was done and the abdomen closed with drain in the sub hepatic space and the drain tube was removed on the fourth post-operative day. The post-operative period was hectic and he developed serous fluid collection at incision site which was managed by simple drainage. On the 12th post-operative day the child was discharged on triple Helicobacter pylori therapy (omeprazole plus amoxicillin and claritromycin for 1 week followed by omeprazole for 2 weeks). Oral deferasirox was stopped and serum ferritin level was monitored. Serum gastrin level in post-operative period was normal. At 3 moths follow-up upper G I endoscopy was normal and serology and biopsy for H. pylori were negative. The chelation treatment was restarted based on an increasing level of ferritine (950 ng/ml), due to the iron overload of the hypertransfusion regime. To prevent peptic ulcer, omeprazole was continued. So far the patient has no complaints related to gastrointestinal tract.

Discussion

Peptic ulcer disease is uncommon in children and rarely suspected as a cause of abdominal complaints in this age group. The diagnosis is, therefore, done almost immediately when the child develops complications; peptic ulcer disease is rarely included in the differential diagnosis of pediatric patients.[6] Peptic ulcer disease is either primary (intrinsic) or secondary (extrinsic) depending on the etiology. Ulcer disease in children less than 10 years of age is usually secondary and is located predominantly in the duodenum. However, if a primary ulcer is present in this age group, it is usually gastric in origin. In children 10 years or older, primary ulcer disease is more common.[37] The vast majority of primary duodenal ulcers are associated with H. pylori infection of the gastric antral mucosa.[78] Secondary ulcer disease occurs as a result of some external predisposing cause, such as medications or stress. Associated medications include aspirin, non-steroidal anti-inflammatory drugs, and steroids. In infants, stress-induced ulcers are often caused by traumatic delivery, respiratory or cardiac distress, sepsis, hypoglycemia, or dehydration. In older children, life-threatening illness and trauma are the main causes; ulcers associated with intracranial pathology (Cushing's ulcer) or burns (Curling's ulcer) have been well described. Since, secondary ulcer disease predominantly occurs in the duodenum, it is more likely to present catastrophically, with hemorrhage or perforation as the initial features. In one study, 30% of patients had perforation on initial presentation.[9] Often, exploratory laparotomy is the only way to diagnose patients with secondary ulcer disease because of the presentation of patients with an acute abdomen.

Iron chelation therapy is essential in patients with â-thalassaemia major undergoing regular transfusion therapy to prevent the serious clinical sequelae of transfusional iron overload, such as cardiac failure. Deferasirox has a safe medication profile in pediatrics. Gastro-intestinal complaints (mainly vomiting and diarrhea) are reported in phase II trials in pediatric patients with beta-thalassemia major receiving deferasirox.[5] Bauters et al. reported a case of gastric ulcer in a 10-year-old girl with thalessemia major who was on oral deferasirox.[10] To our knowledge, perforated duodenal ulcer secondary to use of deferasirox has not been reported in past. In literature, there is unknown association between peptic ulcers and beta-thalassemia major. Our patient was not on any other medication at the time of presentation hence perforated duodenal ulcer presenting with features of peritonitis was most probably secondary to use of oral deferasirox which he was on since past 3 year, which was also assessed as probable on WHO-UMC causality assessment scale.[11]

Presentation of peptic ulcer disease in children covers a broad spectrum ranging from subtle, and thus overlooked and under diagnosed, to catastrophic, as in this case. It is, therefore, very important for the emergency physician to realize the potential morbidity and mortality of this disease and be aware of the spectrum of presentation for primary and secondary pediatric ulcer disease. Use of antacids (ranitidine or omeprazole) for prevention of peptic ulcer might be an option in patients who are taking oral deferasirox so that similar catastrophic events like perforation and bleeding, which can be classified as a probable complication according to WHO-UMC casuality assessment criteria can be prevented.