遗传性胰腺炎发病机制及治疗研究进展
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摘要
遗传性胰腺炎是急性或慢性胰腺炎的一种罕见类型,临床表现与其他原因所致胰腺炎类似。1996年Whitcomb首次报道PRSS1基因突变为遗传性胰腺炎的病因。随后SPINK1基因、CFTR基因、CTRC基因被报道与遗传性胰腺炎相关,但它们是否为遗传性胰腺炎的致病基因仍存在争议。PRSS1编码阳离子胰蛋白酶原,该基因的突变可能导致胰蛋白原激活增加或失活减少,引起临床胰腺炎。目前已经报道了超过20种PRSS1的致病性突变,其中最常见的突变位点为R122H、N29I、和A16V。遗传性胰腺炎发病年龄较早,通常在20岁前起病,平均发病年龄为10岁,进展为慢性胰腺炎的平均年龄为20岁,50岁以后胰腺癌发病风险明显增加。遗传性胰腺炎患者的监管包括:避免环境触发,胰腺内分泌和外分泌功能不全的治疗,疼痛的管理,内镜或手术治疗以及胰腺癌的监测。笔者重点就PRSS1相关性遗传性胰腺炎的发病机制、治疗研究进展及疾病管理等方面进行综述。
Hereditary pancreatitis is a rare type of acute or chronic pancreatitis with clinical symptoms similar to pancreatitis caused by other causes. In 1996, Whitcomb firstly reported that mutation of PRSS1 is the cause of hereditary pancreatitis. Subsequently, SPINK1, CFTR and CTRC were reported to be associated with hereditary pancreatitis, but whether they are the causative genes of hereditary pancreatitis remains controversial. PRSS1 encodes cationic trypsinogen, and mutations in this gene may result in increased trypsin activation or reduced inactivation, causing clinical pancreatitis. More than 20 pathogenic mutations of PRSS1 have been reported, and the most common mutation sites are R122 H, N29 I and A16 V. The onset of hereditary pancreatitis occurs at a younger age, and usually before the age of 20, with an average onset age of 10 years. The average age for developing chronic pancreatitis is 20 years, and the risk for progressing to pancreatic cancer is dramatically increased after 50 years of age. Management of patients with hereditary pancreatitis includes avoidance of environmental triggers, therapy for endocrine and exocrine insufficiency, pain management, endoscopic or surgical treatment and surveillance for pancreatic cancer. Here, the authors mainly address the research progress of the pathogenesis and treatment as well as disease management of PRSS1-related hereditary pancreatitis.
Hereditary pancreatitis is a rare type of acute or chronic pancreatitis with clinical symptoms similar to pancreatitis caused by other causes. In 1996, Whitcomb firstly reported that mutation of PRSS1 is the cause of hereditary pancreatitis. Subsequently, SPINK1, CFTR and CTRC were reported to be associated with hereditary pancreatitis, but whether they are the causative genes of hereditary pancreatitis remains controversial. PRSS1 encodes cationic trypsinogen, and mutations in this gene may result in increased trypsin activation or reduced inactivation, causing clinical pancreatitis. More than 20 pathogenic mutations of PRSS1 have been reported, and the most common mutation sites are R122 H, N29 I and A16 V. The onset of hereditary pancreatitis occurs at a younger age, and usually before the age of 20, with an average onset age of 10 years. The average age for developing chronic pancreatitis is 20 years, and the risk for progressing to pancreatic cancer is dramatically increased after 50 years of age. Management of patients with hereditary pancreatitis includes avoidance of environmental triggers, therapy for endocrine and exocrine insufficiency, pain management, endoscopic or surgical treatment and surveillance for pancreatic cancer. Here, the authors mainly address the research progress of the pathogenesis and treatment as well as disease management of PRSS1-related hereditary pancreatitis.
引文
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[17]SzabóA,Sahin-Tóth M.Increased activation of hereditary pancreatitis-associated human cationic trypsinogen mutants in presence of chymotrypsin C[J].J Biol Chem,2012,287(24):20701-20710.doi:10.1074/jbc.M112.360065.
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[22]Le Maréchal C,Masson E,Chen JM,et al.Hereditary pancreatitis caused by triplication of the trypsinogen locus[J].Nat Genet,2006,38(12):1372-1374.doi:10.1038/ng1904.
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[25]Sossenheimer MJ,Aston CE,Preston RA,et al.Clinical characteristics of hereditary pancreatitis in a large family,based on high-risk haplotype.The Midwest Multicenter Pancreatic Study Group(MMPSG)[J].Am J Gastroenterol,1997,92(7):1113-1116.
[26]Sahin-Tóth M,Tóth M.Gain-of-function mutations associated with hereditary pancreatitis enhance autoactivation of human cationic trypsinogen[J].Biochem Biophys Res Commun,2000,278(2):286-289.doi:10.1006/bbrc.2000.3797.
[27]Rebours V,Boutron-Ruault MC,Schnee M,et al.The natural history of hereditary pancreatitis:a national series[J].Gut,2009,58(1):97-103.doi:10.1136/gut.2008.149179.
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[29]Witt H,Luck W,Becker M.A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis[J].Gastroenterology,1999,117(1):7-10.
[30]Teich N,Ockenga J,Hoffmeister A,et al.Chronic pancreatitis associated with an activation peptide mutation that facilitates trypsin activation[J].Gastroenterology,2000,119(2):461-465.
[31]Nemoda Z,Sahin-Tóth M.Chymotrypsin C(caldecrin)stimulates autoactivation of human cationic trypsinogen[J].J Biol Chem,2006,281(17):11879-11886.doi:10.1074/jbc.M600124200.
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