Report of cases
Received: 07 May 2024
Accepted: 24 May 2024
DOI: https://doi.org/10.22516/25007440.1211
Abstract: Pancreatitis, or inflammation of the pancreas, is a common reason for medical consultation, particularly in emergency departments when patients present with abdominal pain. It represents a significant financial burden on healthcare systems, as one in three cases progresses to moderate or severe pancreatitis, leading to increased morbidity, mortality, and complications. Currently, the primary causes of pancreatitis include obstructive biliary and non-biliary factors, resulting from reflux and the absence of enzyme flow into the intestine. This leads to enzyme activation within the pancreatic tissue, causing self-digestion. Alcohol consumption and hypertriglyceridemia contribute to cellular toxicity due to the metabolic breakdown of these substances. Drug-induced pancreatitis is a rare condition associated with antibiotics, analgesics, and antidepressants. Deferasirox, an iron chelator primarily used in patients requiring frequent blood transfusions to prevent iron overload, has rarely been linked to pancreatitis. However, available data suggest a possible correlation, and the pharmaceutical manufacturer lists pancreatitis as a potential adverse effect in the drug’s technical specifications. This report presents the case of a 71-year-old female patient who developed moderate to severe pancreatitis without major complications. Physicians ruled out the most common causes of pancreatitis and concluded that the triggering factor was the iron-chelating agent deferasirox.
Keywords: Pancreatitis, acute pancreatitis, abdominal pain, deferasirox, Exjade.
Resumen: La inflamación del páncreas, llamada pancreatitis, es un motivo de consulta común, y es uno de los más representativos cuando el dolor abdominal es el motivo de consulta para acudir a una sala de emergencia; representa un alto costo para todo el sistema de salud, pues solo uno de cada tres pacientes cursa con pancreatitis moderada a grave, con un aumento significativo de morbimortalidad y tasa de complicaciones. Actualmente, las principales etiologías incluyen causas obstructivas de origen biliar o no biliar por reflujo y ausencia de flujo de enzimas al intestino que se activan en el parénquima degradándolo, el alcoholismo y la hipertrigliceridemia son mecanismos relacionados con la toxicidad celular luego del metabolismo de estas moléculas. La pancreatitis inducida por fármacos es una afección rara relacionada con antibióticos, analgésicos y antidepresivos. El deferasirox es un quelante del hierro especialmente utilizado en pacientes que necesitan múltiples transfusiones para evitar la sobrecarga de hierro. Ha sido poco correlacionado con el desarrollo de pancreatitis, aunque existen datos que podrían corroborarla; adicionalmente la farmacéutica responsable de su producción incluye esta entidad como una posible complicación en los aspectos técnicos. Este artículo presenta el caso de una paciente de 71 años de edad que desarrolló pancreatitis moderada a grave sin complicaciones importantes. Los médicos descartaron las causas más frecuentes de pancreatitis, por lo que concluyeron que el agente desencadenante fue el quelante del hierro deferasirox.
Palabras clave: Pancreatitis, pancreatitis aguda, dolor abdominal, deferasirox, Exjade.
Introduction
Inflammation of the pancreas, known as pancreatitis, is a common condition. It is the leading cause of gastrointestinal-related consultations in the United States, resulting in significant morbidity and mortality, as well as increased healthcare costs. This condition accounts for up to 275,000 hospitalizations annually, with an incidence ranging from 13 to 45 cases per 100,000 inhabitants per year in the United States1,2.
It is important to note that the three abdominal diagnoses associated with the highest healthcare costs are gastrointestinal bleeding, gallbladder disease, and pancreatitis, representing an expenditure of over 12 billion dollars annually. In 2018, pancreatitis accounted for up to 195,000 emergency department visits and 562,000 outpatient visits in the United States, with up to 65.6% of these patients requiring hospitalization, and an average cost per hospitalization of 23,472 dollars per patient3,4.
In Colombia, the two main etiologies are biliary pancreatitis and alcohol-related pancreatitis. Most cases are mild and follow a satisfactory course; however, up to 30% are moderate to severe cases, with mortality rates rising dramatically from 5% to 35%. In the country, the incidence is 34 cases per 100,000 inhabitants5,6.
In developed countries, gallstone obstruction has been reported to account for 38% of cases. The mechanism by which pancreatitis develops is related to the lodging of a gallstone in the biliary tract, causing obstruction. This leads to increased ductal pressure and decreased flow, which causes the enzymes produced in the exocrine pancreas to be activated in its interior7. Alcohol is considered the second most common cause, although its pathophysiology is not clearly established. Studies have described that alcohol can be partially metabolized by the exocrine pancreas through oxidative and non-oxidative mechanisms. However, during degradation and elimination, the molecule first binds to fatty acids, forming lipophilic fatty acid ethyl esters. These molecules are well tolerated by pancreatic cells at low concentrations; however, when accumulation occurs, they interfere with the calcium gradient required for exocytosis and also cause mitochondrial toxicity by disrupting oxidative phosphorylation, leading to a secondary drop in adenosine triphosphate levels and resulting in cell death8.
A controversial and rare cause is hypercalcemia. Patients with conditions associated with elevated serum calcium levels may develop pancreatitis, as the deposition of calcium salts is cytotoxic to pancreatic cells. Moreover, the increase in extracellular calcium concentrations enhances the release and subsequent activation of trypsinogen, triggering pancreatic autodigestion9.
Presentation of the case
The patient is a 71-year-old woman with a history of myelodysplastic syndrome associated with chronic anemia, requiring transfusion support every 25 days as indicated by the hematology department. She was being treated with deferasirox. She presented with abdominal pain predominantly in the epigastric region, associated with multiple episodes of vomiting with food content. Management with omeprazole, sucralfate, and sodium alginate was initiated; however, the patient did not respond to treatment, and additional studies were performed (Table 1).
In this context, a diagnosis of pancreatitis was considered, and additional studies were requested to determine the possible cause. An abdominal ultrasound was performed, which did not reveal any abnormalities; however, the pancreas could not be evaluated due to gas interposition. The report noted a postcholecystectomy status. Magnetic resonance cholangiopancreatography (MRCP) showed an increase in pancreatic size and diffuse signal intensity, with alteration of the adjacent fat. Peripancreatic fluid was observed, extending bilaterally to the anterior pararenal space and toward the paracolic gutters, as well as the perihepatic and perisplenic regions. In addition, ectasia of the extrahepatic bile duct was reported, without evidence of any obstructive cause (Figure 1).
Laboratory tests
ALT: alanine aminotransferase; AST: aspartate aminotransferase; CRP: C-reactive protein. Table created by the authors.
Figure 1
Abdominal MRCP: The pancreas shows a diffuse increase in size and signal intensity, with alteration of the adjacent fat. There is peripancreatic fluid extending bilaterally into the anterior pararenal spaces and along the paracolic gutters, as well as into the perihepatic and perisplenic regions. Images property of the authors.
The patient presented clinical and paraclinical findings consistent with pancreatitis. After ruling out the most common causes, a consultation was requested with the gastroenterology department, where it was determined that this was a case of moderately severe pancreatitis. As further studies were carried out to determine the origin, an endoscopic ultrasound was performed, which reported acute pancreatitis without biliary duct dilatation, without lithiasis, with absence of the gallbladder, and a normal papilla.
The patient showed gradual but steady improvement, with increasing tolerance to the initial diet and its progression, along with better control of abdominal pain. Since no typical causes of pancreatitis were found, the patient’s medication history was reviewed again. A possible association between the iron chelator and pancreatitis was identified. These reports describe that this association is more frequent in pediatric patients, probably due to the higher incidence of hematologic disorders, although there remains a risk when using deferasirox in adult patients. The hematology team agreed with this etiological approach and discontinued the administration of this drug. The patient ultimately had a favorable clinical course, with normalization of biochemical parameters, and was discharged from the hospital. The next step is to assess whether the patient will require reinitiation of an iron chelator due to the frequent and multiple transfusions, while considering the risk of recurrent pancreatitis.
Discussion
Deferasirox is an iron-chelating drug developed by Novartis and approved by the U.S. Food and Drug Administration (FDA) in 2005 for the management of iron overload, a common condition in patients requiring frequent blood transfusions due to various pathologies10. It works by forming irreversible bonds with ferric iron in a 1:1 ratio, leading to the subsequent fecal elimination of the formed complex, thereby removing the excess iron. It is important to mention that there are no endogenous systems that respond to the increase in iron levels, there are only mechanisms to store it11.
The first study demonstrating its efficacy was published in The Lancet in 2003, which included patients with β-thalassemia requiring frequent transfusion support. The results showed that, compared to a placebo, it reduced iron levels and also had an appropriate safety profile12. Later, in 2006, a study was published in the journal Blood that included patients with β-thalassemia and compared deferasirox with deferoxamine in terms of reducing hepatic iron concentration. This study demonstrated slightly greater effectiveness, though not statistically significant; however, deferasirox is an oral agent, which, compared to slow infusion or subcutaneous administration, also showed an appropriate safety profile. Gastrointestinal symptoms were common but self-limited in less than eight days. The administration of these drugs also resulted in a mild elevation of transaminases in most patients, and in two cases, treatment was discontinued due to drug-induced hepatitis13.
In the randomized studies, pancreatitis related to deferasirox was never mentioned. However, there is a follow-up study in which one case of acute pancreatitis was reported as an adverse effect14. In 2015, the Health Sciences Authority (HSA) issued an alert describing a review of VigiBase, the World Health Organization’s (WHO) database, which identified 14 possible cases of pancreatitis related to this drug. In three of these cases, confusion with other medications could have occurred. However, in the remaining 11 cases, deferasirox was the only drug associated, prompting the company to investigate the correlation. Health professionals were advised to exercise caution when using the drug and consider the potential risk, even though it is a rare event15,16. In 2021, Novartis developed a manual for patients using deferasirox that includes pancreatitis as a possible adverse effect of this agent17, and various monitoring entities included this potential adverse effect in the medication’s precautions18,19.
In the presented case, the patient was definitively diagnosed with pancreatitis based on the clinical presentation, laboratory results, and imaging. She was managed by a multidisciplinary team, including specialists in internal medicine, gastroenterology, and hematology. The primary causes of pancreatitis were objectively ruled out, and the treating team, based on evidence and clinical experience, determined it to be a case of drug-induced pancreatitis caused by deferasirox.
Conclusions
Drug-induced pancreatitis can be a challenging diagnosis, especially in the case of iron chelators, given their limited use and relative infrequency. It is important not to overlook common causes and to subsequently individualize the diagnosis for each patient. In these cases, having a multidisciplinary team of experts is crucial to offer the best approach and management for each patient. This report does not aim to discourage the use of the drug in question, but rather to inform the scientific community about the existence of this potential condition.
References
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Notes
Author notes
*Correspondence: Juan Sebastián Matamoros-Muñoz. sebasmatamoros5vf.sm@gmail.com
Conflict of interest declaration
