Pancreas Divisum: Beyond the Apparent

Abstract

Acute recurrent pancreatitis is a common clinical problem. The etiology and clinical management vary widely. Pancreas divisum is the most common congenital anomaly of the pancreas. However, only a small percentage of individuals with pancreas divisum develop acute or recurrent pancreatitis. Clinical manifestations range from isolated episodes of acute recurrent pancreatitis to chronic pancreatitis, and in some cases unexplained pain without any recognizable inflammation. The variations in clinical presentation, clinical progression of the disease, and responses to endoscopic or nonendoscopic treatments are not entirely predictable. 1 These facts have led to substantial controversy about the association of pancreas divisum with pancreatic disease. They lead us to believe that mere presence of an anatomic anomaly is not in itself sufficient and there have to be other disease modifiers or cofactors that are responsible for pancreatic injury. Environmental insults such as oxidative stresses could play a role, however, these do not seem to be universally reproducible. A key may lie in the genetic make up of the individual. In this issue of the journal, Garg and colleagues 2 have investigated the association of genetic mutations and acute recurrent pancreatitis in individuals with pancreas divisum. They have tested for genetic mutations known to be associated with pancreatitis: cystic fibrosis transmembrane conductance regulator gene (CFTR), cationic trypsinogen (PRSS1), and serine protease inhibitor Kazal type 1 (SPINK1) gene. This study was conducted in a tertiary referral center in Northern India. They studied 12 subjects with pancreas divisum and acute recurrent pancreatitis. Their control group included patients with acute recurrent pancreatitis but no pancreas divisum, patients with chronic pancreatitis due to other causes, and healthy volunteers. Mutations in individuals with asymptomatic pancreas divisum were not evaluated. Detailed work-up was carried out including analysis for the presence of microcrystals in the bile before considering etiology of pancreatitis to be idiopathic. All subjects with pancreas divisum and acute recurrent pancreatitis underwent endoscopic retrograde cholangiopancreatography with minor papillotomy and temporary stenting of the dorsal duct. Response to endoscopic therapy was defined as reduction in >50% of acute pancreatitis episodes/year. Prevalence of SPINK1 gene mutations was found to be similar in patients with recurrent acute pancreatitis with or without pancreas divisum and those with chronic pancreatitis. However, only 1 in 50 of the control group had SPINK1 gene mutation. Polymorphism in the CFTR gene was seen at a higher frequency in those with pancreas divisum. One could argue that the ideal control should be those with pancreas divisum but without symptoms. From clinical practice, we know that these controls would be hard to identify without the use of secretin-stimulated magnetic resonance cholangiopancreatography or other expensive noninvasive imaging. SPINK1 gene mutations along with mutations in CFTR have been previously shown to occur at a higher frequency in patients with idiopathic chronic and acute recurrent pancreatitis. 3,4 Some animal studies have demonstrated that genetic mutations in CFTR might be responsible for an increased inflammatory response in mice. 5 SPINK1 gene mutations were previously found in a Finnish study to occur at a higher rate in those with acute pancreatitis, suggesting that the SPINK1 gene mutation probably enhances the susceptibility to acute pancreatitis. 6 This study of Garg and colleagues raises a very thought-provoking question: is pancreatitis in patients with pancreas divisum related to the outflow obstruction at the minor papilla? From previous studies we know that only a minority of those with pancreas divisum are symptomatic and the responses to therapy are not uniformly the same despite minor papillotomy, which should relieve any obstruction. The findings of this and other studies suggest an etiology other than a simple mechanical obstruction alone. In this study, responses to endoscopic therapy were similar to those already reported, with significant improvement in approximately 70% of patients. 7 This study involved numbers that were too small to examine whether the response to therapy is predictable based on the genetic mutations. Despite the