| Chronic pancreatitis (CP) is characterized by progressive pancreatic damage that eventually resμlts in significant impairment of exocrine as well as endocrine functions of the gland.The most common disease associations with chronic pancreatitis include alcohol abuse, hypercalcemia, and immunological events. Idiopathic chronic pancreatitis(ICP) is diagnosed in up to 25% of patients with chronic pancreatitis by exclusion of other potential causes, including rare ones. Due to considerable progress in our understanding of hereditary and autoimmune mechanisms for development of chronic pancreatitis, the specific etiology of chronic pancreatitis can be determined in an increasing proportion of cases. Nevertheless, the etiopathogenesis of idiopathic chronic pancreatitis frequently remains obscure. Layer et al. observed that patients with early-onset ICP had a relatively mild course with slower development of exocrine and endocrine insufficiency than the late-onset form.But Y-T Chang et al. described that patients with early-onset ICP had a much higher SPINK1 mutation rate and a more severe phenotype than those with late-onset ICP, according to genotype-phenotype and statistical analyses.Thus far, previous studies have attempted to explain the early-onset mechanism of the ICP by clinical investigation and genotype-phenotype analysis. SPINK1 mutation was considered a key factor leading the early-onset of the ICP in part of researches. However, we found that a pair of monozygotic twins with ICP had different disease onset ages exceeding 30 years. So, we suppose that other factors play more important role in early-onset mechanism of ICP, rather than gene mutation.We used sequencing analysis to detect the common mutations in the cationic trypsinogen gene (PRSS1) and serine protease inhibitor Kazal type 1 (SPINK1) gene, which may be associated with ICP of the Han popμlation in China, and verified the serum level of SPINK1 by ELISA. Next, we screened the differentially expressed proteins and microRNAs from plasma samples of early-onset and late-onset ICP by proteomic analysis and microarray. Combined with these bioinformatics methods, we validated that the regμlatory effects of microRNAs were involved in the early-onset mechanism of the ICP by in vitro experiments.The c.194+2T>C variant of SPINK1 was the only mutation found in our patients with ICP. Though statistical analysis showed that patients with early-onset ICP had a higher mutation rate than those with late-onset disease (60.0% vs. 25.0%, p<0.001), there was no significant difference in plasma SPINK1 expression between these two groups. However, the expression of plasma glutathione peroxidase (GPx3) in early-onset ICP patients was markedly lower than that in late-onset ones, and the levels of plasma 8-OHdG and MDA in the early-onset patient group were significantly increased as compared to those of the late-onset patients and healthy controls.The microRNA chip analysis showed that the level of hsa-miR-453 was lower in late-onset patients when compared to the early-onset group. In vitro experiments confirmed that hsa-miR-453 can effectively inhibit luciferase activity of pMIR-reporter-GPx3.Here, using genomics, proteomics and microRNA chip analysis, we demonstrated that the c.194+2T>C variant of SPINK1was not the only determinant factor for early-onset ICP but rather that GPx3 played a key role in this etiopathogenesis of early-onset disease by diminishing antioxidant activity. Moreover, through in vitro experiments, we found that up-regμlated hsa-miR-453 led to lowered expression of GPx3. This finding provides methods and new ideas for further study of the early-onset mechanisms of ICP.Because the etiology of chronic pancreatitis is complicated, the exact mechanism of disease has not been fμlly clarified, the treatment of chronic pancreatitis is still a problem. Endoscopic transpapillary pancreatic duct drainage is the procedure of choice for dilated pancreatic duct in patients with chronic pancreatitis. However, it may be unsuccessfμl in 5-10% of cases. Recently the use of Eus-guided drainage of pancreatic duct has been reported, but it is not clear whether it is feasible for this technique to find more widespread use as an alternative to failed ERCP. We herein describe our experience with a case of chronic pancreatitis complicated by Whipple procedure with dialed pancreatic duct successfμlly treated by Eus-guided pancreatic duct drainage.This paper is divided into four parts: Part one: The genetic analysis of the chronic pancreatitis of Han popμlation in mainland China; Part two: MicroRNA-453 down-regμlates Plasma Glutathione peroxidase in early-onset idiopathic chronic pancreatitis patients: a potential disease mechanism? Part three: Endoscopicμltrasound-guided transgastric pancreatic duct drainage after Whipple surgery in a patient with chronic pancreatitis; Part four: Review of the etiology,treatment of chronic pancreatitis and the relationships of the chronic pancreatitis and the pancreatic cancer.
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