Molecular Genetics of Chronic Pancreatitis

Abstract

Chronic pancreatitis is a progressive inflammatory condition of the pancreas that results in impairment of both exocrine and endocrine functions of the gland. The finding that a mutation in the cationic trypsinogen gene (PRSS1) causes hereditary pancreatitis was a major breakthrough that stimulated intensive research into the genetics of chronic pancreatitis. Further diseaseā€causing mutations were identified in the PRSS1 gene, and mutations in novel genes (SPINK1, CFTR, CTRC, CASR) have been described in patients with idiopathic chronic pancreatitis. Genetic and biochemical studies highlighted the importance of the tightly regulated balance between trypsin activation and inactivation in the pathogenesis of pancreatitis.

Keywords: chronic pancreatitis; hereditary pancreatitis; cationic trypsinogen; SPINK1; CTRC

Figure 1.

The trypsin‐dependent pathological model of chronic pancreatitis. Early activation of trypsinogen to trypsin within the pancreas plays a crucial role in the development of pancreatitis (red arrow). Trypsinogen activation is prevented in normal zymogen granules, promoted in trypsinogen (PRSS1) mutations, and in trypsin in the presence of calcium. There are two early defence mechanisms to protect the organ against intracellular trypsin activity: trypsin degradation within the acinar cell and trypsin secretion into the duct. Trypsin will degrade itself in low calcium in the presence of CTRC. Thus calcium levels play a key regulatory role, and calcium is regulated by CASR and alcohol (EtOH). If trypsin is secreted, the rapid flushing of trypsin out of the duct is facilitated by CFTR. If trypsin activity is retained to that point that significant injury occurs, then an acute inflammatory response (AIR) is generated. The AIR upregulates SPINK1, which will inhibit trypsin directly, both inside and outside of the acinar cell (green lines, stimulation; red lines, inhibition; dashed lines, stimulation in the absence of inhibition). Figure by Dr. Whitcomb, all rights reserved.

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Further Reading

Deng X, Wang L, Elm MS et al. (2005) Chronic alcohol consumption accelerates fibrosis in response to cerulein‐induced pancreatitis in rats. American Journal of Pathology 166(1): 93–106.

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Whitcomb DC (2006) Polygenetic traits in pancreatic disorders. Endocrinology Metabolism Clinics of North America 35(2): 255–269.

Witt H, Apte MV, Keim V and Wilson JS (2007) Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy. Gastroenterology 132(4): 1557–1573.

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Szmola, Richard, and Whitcomb, David C(Mar 2009) Molecular Genetics of Chronic Pancreatitis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021481]