Department for Internal Medicine, Neurology and Dermatology, Division of Gastroenterology and Rheumatology, Universitätsklinikum Leipzig AöR
Head of Department: prof. Joachim Mössner
Chronic Pancreatitis (CP) is a progressive inflammatory disease of the pancreas leading to permanent impairment of pancreatic exocrine and endocrine function that can result in maldigestion and diabetes mellitus (1). Certainly, one of the most displeasing characteristics of CP are recurring attacks of acute abdominal pain that in some patients pass into a state of chronic pain often hindering patients to participate in a normal working life (2). In the western world the most predominant underlying cause is chronic alcohol abuse. Notably, only about five percent of chronic alcoholics develop CP. Aside chronic alcohol abuse several other factors such as nicotine, hypercalcemia, drugs, trauma and genetic alterations underlie CP. Over a century ago Hans Chiari postulated that chronic pancreatitis is the result of autodigestion of the pancreas, a thesis that is now again supported by genetic studies and functional analyses of genetic variants conducted within the last fifteen years (3). The first pedigree of a family with inherited CP was described in 1952 by Comfort and Steinberg illustrating the influence of genetic alterations that may contribute to the pathogenesis of CP (4). Thereafter, in the end 44 years were necessary until the p.R122H variant of the cationic trypsinogen (PRSS1) was identified in patients with hereditary CP (5). This finding was fundamental for a search for further genetic alterations in CP and also highlighted the importance of a balanced digestive enzyme cascade. In the following years research focused on proteases and anti-proteases that participate in this digestive enzyme cascade as well as on the CFTR gene whose major genetic alterations are responsible for Cystic Fibrosis. Further, “milder” genetic alterations of CFTR were associated with CP. In this rather compact review our we focus on the latest findings in the field of genetics in CP and former findings like association of PRSS1, CFTR and SPINK1 variants are only briefly discussed.
Hereditary CP, an autosomal dominant disease with a clinical penetrance rate of about 60-70% is a very rare form of chronic pancreatitis. The clinical course is different from that in alcoholic CP, since it encompasses an earlier onset and has a slower progression. However, morphological features and laboratory findings do not differ as well as given treatment opportunities. After the first description of the p.R122H variant several other rare variants were found in the PRSS1 gene (6 and references within). Most of the variants seem to cause premature trypsinogen activation in vitro with the consequence of an overweight of proteases since trypsin is able to activate the digestive enzyme cascade. This ssumption was further supported by transgenic animal models that express R122H mutated trypsinogen, because in these animal models elevated serum levels of lipase and amylase were observed (7, 8). However, definite histological changes resembling CP in humans were only found after repetitive supramaximal stimulations with caerulein. However, taken together, functional data in vitro and in vivo support the theory that a disarrangement of the balance between trypsin and its inhibitors in favour of more protease activity is responsible for the development of CP. An important question for the clinician as well as for the patient is whether patients with hereditary CP have a higher risk for the development of pancreatic cancer. Compared to patients with alcoholic CP who have a 20-fold increased lifetime risk of pancreatic cancer the lifetime risk is about 50-fold in patients with hereditary CP (9, 10). In our cohort from Leipzig 3 out of 101 patients with hereditary CP (carrier of the p.R122H mutation) developed pancreatic cancer and this corresponds to a rate of about 1 per 1200 person years among carriers of this mutation (11). In conclusion, the risk to develop pancreatic cancer is elevated in patients with hereditary CP, but the relative risk increase is not unambigously defined so far. Since cigarette smoking is a further evident risk factor for the development of pancreatic cancer, patients with hereditary CP should be strongly encouraged not to smoke (12).
Cystic fibrosis is an autosomal recessive disorder with an incidence in Caucasians of approximately 1 in 2500 live births. In 1989, CFTR was identified as the underlying gene. Since 1-2% of patients with CF suffer from CP it was a logical step to investigate CFTR in CP and in 1998 Sharer and colleagues and Cohn and colleagues were able to show an association of CFTR variants with CP that was replicated thereafter (14-23). According to their effect CFTR variants are divided in five or six classes (I-V/VI) (24, 25). In cystic fibrosis, the most common mutation is F508del, accounting for approximately 66% of all mutated alleles (26). In CP the distribution of CFTR variants does not resemble the distribution found in CF. Most of all rare and mild CFTR variants (class IV-VI) that are found in CP are only seldomly described in CF or congenital aplasia of the vas deferens (CBAVD). Consequently, it was postulated that compound heterozygous CFTR carriers have a distinct elevated risk for the development of chronic pancreatitis, which is even higher when an additional SPINK1 variant is present (27, 28).
Aside other protease inhibitors, SPINK1 seems to be a specific inactivator of intrapancreatic trypsin activity. According to its high expression in the pancreas SPINK1 represented a convincing candidate gene. In 2000 an association of SPINK1 variants with CP was described and the most frequently variant was an amino acid substitution at position 34 from asparagine to serine (30). Carriers of the p.N34S variant were predominantly designated as patients with idiopathic CP in that no other underlying cause for CP could be found. Further studies confirmed the association and even broadened the findings to alcoholic and tropical calcific CP (31-35). Functional investigations with incubation of equimolar quantities of SPINK1 and trypsin revealed formation of a covalent bond between the catalytic serine residue of trypsin and the lysine carboxyl group of the reactive site of SPINK1. After prolonged incubation trypsin activity reappeared. This finding may be explained by the degradation of SPINK1 by trypsin (36). Aside the temporary inhibitor capacity of SPINK1 it has to be kept in mind that the p.N34S variant is found in 1-2% of controls what implicates the assumption that this variant alone might not explain the pathogenesis of CP. Analysis of recombinant SPINK1 carrying the N34S mutation showed an unchanged function of N34S SPINK1 as well as an unchanged trypsin susceptibility indicating that mechanisms other than the conformational change of N34S may underlie the predisposition to CP (37). Above all, it is currently discussed whether p.N34S could display just a marker for another variant (or haplotype) within SPINK1 or an adjacent gene or even in an distinct regulatory region.
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