Howes Nathan, Greenhalf William, Stocken Deborah D, Neoptolemos John P
Department of Surgery, Liverpool University, 5th Floor, University Clinical Department Building, Daulby Street, Liverpool, L69 3GA, United Kingdom.
Gastroenterol Clin North Am. 2004 Dec;33(4):767-87. doi: 10.1016/j.gtc.2004.07.003.
The discovery of PRSS1 mutations in hereditary pancreatitis and analysis of how the genotype affects the presentation and progression of hereditary pancreatitis has led to a better understanding of the pathophysiology of the disease. Patients with hereditary pancreatitis present with symptoms at an early age and have a significant lifetime risk for the development of endocrine and exocrine insufficiency, albeit at a later stage than patients with either idiopathic or alcoholic chronic pancreatitis. There are distinct phenotypic differences between hereditary pancreatitis and with other types of pancreatitis. As many as 80% of patients with symptomatic hereditary pancreatitis have an underlying causative PRSS1 mutation; there are, however, few significant phenotypic differences between these PRSS1 mutations. The R122H mutation is the most common PRSS1 mutation observed, and patients with the R122H mutation present earlier. This, however, does not necessarily translate into a more aggressive disease with respect to complications of chronic pancreatitis. Indeed, the age of presentation of symptoms may be a poor surrogate for predicting outcome, as inherited disorders of trypsinogen may cause subclinical attacks of pancreatitis, which ultimately lead to pancreatic destruction and dysfunction. All patients, irrespective of whether they carry a PRSS1 mutation, are at significant risk of developing pancreatic ductal adenocarcinoma. The risk appears to be insignificant below the age of 40 years, but it increases incrementally thereafter. Significantly, the risk of pancreatic cancer is not related to PRSS1 mutation type and does not appear to be related to the mode of inheritance. The role of SPINK1 mutations in modifying the expression of PRSS1 mutations is unclear but appears to be of clinical importance. It is unlikely that they act as causative mutations per se, at least in the Western form of the disease. Additionally, they do not appear to have an impact on the penetrance of PRSS1 gene mutations in hereditary pancreatitis.
遗传性胰腺炎中PRSS1突变的发现以及对该基因型如何影响遗传性胰腺炎的表现和进展的分析，使人们对该疾病的病理生理学有了更好的理解。遗传性胰腺炎患者在早年就会出现症状，并且终生有发生内分泌和外分泌功能不全的重大风险，尽管这一风险出现的时间比特发性或酒精性慢性胰腺炎患者要晚。遗传性胰腺炎与其他类型的胰腺炎之间存在明显的表型差异。多达80%有症状的遗传性胰腺炎患者存在潜在的致病性PRSS1突变；然而，这些PRSS1突变之间几乎没有明显的表型差异。R122H突变是观察到的最常见的PRSS1突变，携带R122H突变的患者发病更早。然而，就慢性胰腺炎的并发症而言，这并不一定意味着疾病更具侵袭性。事实上，症状出现的年龄可能不是预测预后的良好指标，因为遗传性胰蛋白酶原紊乱可能导致胰腺炎的亚临床发作，最终导致胰腺破坏和功能障碍。所有患者，无论是否携带PRSS1突变，都有发生胰腺导管腺癌的重大风险。40岁以下时，这种风险似乎不显著，但此后会逐渐增加。值得注意的是，胰腺癌的风险与PRSS1突变类型无关，也似乎与遗传方式无关。SPINK1突变在修饰PRSS1突变表达中的作用尚不清楚，但似乎具有临床重要性。至少在该疾病的西方形式中，它们本身不太可能作为致病突变起作用。此外，它们似乎对遗传性胰腺炎中PRSS1基因突变的外显率没有影响。
