Clinical and Radiological Outcome of Patients Suffering From Chronic Pancreatitis Associated With Gene Mutations Luca Frulloni, MD, PhD,* Chiara Scattolini, MD,Þ Rossella Graziani, MD,þ Giulia Martina Cavestro, MD,§ Cecilia Pravadelli, MD,* Antonio Amodio, MD,* Riccardo Manfredi, MD,þ Aldo Scarpa, MD,|| and Italo Vantini, MD* Objectives: Cystic fibrosis transmembrane conductance regulator (CFTR), cationic trypsinogen gene (PRSS1), and serine protease inhibitor kazal type 1 (SPINK1) gene mutations have been associated with chronic pancreatitis (CP). The aim of this study was to compare clinical and radiological findings in sporadic CP with (CPgm) and without (CPwt) gene mutations. Methods: Data from patients observed between 2001 and 2006 were collected. All patients were tested for 25 CFTR gene mutations, for R122H and N29I on the PRSS1 gene, and for N34S mutation on the SPINK1 gene. Results: We found 34 (17.2%) of 198 patients with CPgm, 23 (11.6%) of them on the CFTR gene, 11 (5.6%) on the SPINK1, and none on the PRSS1 gene. The age at clinical onset was younger in CPgm (36.2 T 17.2 years) than in CPwt (44 T 12.6 years; P = 0.005). There were more heavy drinkers among CPwt (33%) than among CPgm (9%; P = 0.003), and the same applied to smokers (69% vs 33%, respectively; P G 0.0001). In CPgm group, the onset of pancreatic calcifications was observed more frequently in drinkers and/or smokers. Exocrine and endocrine insufficiency occurred less frequently and later in CPgm than in CPwt patients. Conclusions: Clinical and radiological outcome differ in CPgm compared with CPwt. Alcohol, even in small quantities, and cigarette smoking influence the onset of pancreatic calcifications. Key Words: pancreatitis, mutation, cystic fibrosis transmembrane conductance regulator gene, pancreatic secretory trypsin inhibitor gene, cationic trypsinogen gene, exocrine pancreatic insufficiency, diabetes (Pancreas 2008;37:371Y376) T he pathogenesis of chronic pancreatitis remains obscure, although many hypotheses have been advanced. 1 In the last decade, several particular forms of chronic pancreatitis have been identified, such as autoimmune pancreatitis, 2 groove pancreatitis or cystic dystrophy of the duodenal wall, 3Y5 chronic pancreatitis associated with previous episodes of necrotizing pancreatitis, and chronic pancreatitis associated with gene mutations, leading some authors to adopt the term of Binflammatory diseases of the pancreas.[ 6 Mutations in several genes have been found in association with chronic pancreatitis. 7Y32 Two main mutations (R122H and N29I) 7,11,15,17,18,20,21,26 on the cationic trypsinogen gene (PRSS1) have been detected in patients with hereditary pancreatitis. It has been postulated that these mutations may induce a loss of normal trypsin inactivation, or a trypsin more resistant to inactivation, secondary to a modification in the shape of the molecule. 7,33 In both cases, the trypsin-mediated autodigestive process in the pancreas may be facilitated and results in the clinical onset of acute pancreatitis, 7 which may recur and in which chronic pancreatitis sets in. Several other mutations on the PRSS1 gene were found to be associated with familial and hereditary pancreatitis (A16V, D22G, K23R, R122C, and N29T), 11,17,18,21,27,28 but their clinical significance has yet to be fully elucidated. 34 Mutations on the serine protease inhibitor kazal type 1 (SPINK1) gene have been found in patients with idiopathic chronic pancreatitis. 10,12,16,22,23 This gene codifies for the pancreatic secretory trypsin inhibitor, a peptide capable of blocking the active site of trypsin. Like patients with PRSS1 gene mutations, carriers of this mutation may have a loss of intrapancreatic trypsin inhibition that predisposed them to recurrent episodes of pancreatitis and subsequently to chronic pancreatitis. 35,36 Several mutations on the cystic fibrosis transmembrane conductance regulator (CFTR) gene are more frequent in patients with idiopathic chronic pancreatitis than in the general population. 8,24,25,30 The pathogenic mechanism leading to recurrent and chronic pancreatitis is still not clearly under- stood, although a thickening of the pancreatic juice leading to functional obstruction of the pancreatic ductal system has been postulated, or a disruption of the intracellular acinar exocytosis process. 37,38 Recently, mutations on chymotrypsin C (CTRC) gene, an enzyme identical to enzyme Y and playing a role on a second line defence mechanism against premature intrapan- creatic activation of trypsinogen isoforms by degrading trypsin/trypsinogen after saturation of SPINK1, has been found to be associated with chronic pancreatitis. 31,32 ORIGINAL ARTICLE Pancreas & Volume 37, Number 4, November 2008 371 Received for publication December 2, 2007; accepted May 7, 2008. From the Departments of *Biochemical and Surgical Sciences, †Surgical and Gastroenterological Sciences, and ‡Radiology, University of Verona, Verona; §Department of Clinical Sciences, University of Parma, Parma; and ||Department of Pathology, University of Verona, Verona, Italy. Reprints: Luca Frulloni, MD, PhD, Cattedra di Gastroenterologia Universita ` di Verona Piazzale La Scuro, 10, 37134 Verona, Italy (e-mail: luca.frulloni@ univr.it). Copyright * 2008 by Lippincott Williams & Wilkins Copyright @ 2008 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.