Clinical study for the pathogenesis of idiopathic chronic pancreatitis -- Analysis on the pathogenesis of familial chronic pancreatitis using the molecular biological methods

为了探讨慢性胰腺炎（CP）的发病机制，我们确定了什么样的遗传异常影响家族性CP。我们回顾了报告的年轻胰腺炎患者和胰腺疾病的情况下，在一个家庭。日本报告了来自38个家庭的105例CP患者，其中有两例和两例以上CP病例。56例遗传性CP患者来自15个家系，其中2代以上有2个以上血亲发生胰腺炎。在日本，家族性CP占所有CP病例的0.7%-1.5%。共有3个家庭的14名患者在我们的诊所。在一个有6例CP患者的家族中，我们发现了两例新的男性患者（29岁和24岁，两名患者的儿子），经胰腺钙化和胰管不规则扩张证实。对CP兄弟病例的HLA抗原分析表明，A、B、C、DR位点的HLA抗原具有一致性，它们都具有A24、BW 52、BW 54、CW 1、DR 2和DR 4。在同一个家系中，有1/4对父母和子女显示出相同的C-和DR-位点（CW 1，CW 3，DR 4，DRW 9）。在我们的临床中，家族性CP的HLA DR-2型频率增加。HLA与CP的发病因素无明显关系，我们认为防御机制在CP的发病中起主要作用。从外周血白细胞中提取基因组DNA，用EcoRI、HindIII、BamHI、StagI酶切，Southern杂交分析表明，两个家系的胰腺分泌型胰蛋白酶抑制剂（PSTI）和Reg基因组DNA均未发生重排或缺失。采用聚合酶链反应（PCR）技术从基因组DNA中扩增PSTI基因的4个外显子，并直接测序。在家族性CP的PSTI基因中观察到一个单碱基改变。但我们尚未证实该区域影响蛋白质的合成。

To investigate the pathogenesis of chronic pancreatitis(CP), we determined what kind of genetic abnormality affected the familial CP.We reviewed the reports of young pancreatitis patients and cases of pancreatic disorders in a family. One hundred five patients from 38 families with two and more than two cases of CP have been reported in Japan. There were 56 hereditary CP patients from 15 families, in whom pancreatitis occurred in more than two blood-related persons in over 2 or more generations. Familial CP accounted for 0.7%-1.5% of all cases of CP in Japan. There were 14 patients from 3 families in our clinic. In a kindred having 6 CP patients, we found newly two male patients (29 and 24 years old, two patient's sons) proved by pancreatic calcification and irregular dilatation of the pancreatic duct.No genetic abnormality in the familial CP has been reported. Analysis on the HLA antigens of cases of brothers with CP showed the co-incidence in locus A, B, C, and DR, i.e., both of them possessing A24, BW52, BW54, CW1, DR2 and DR4. One out of four pairs os child and parent in one kindred revealed the same C- and DR-locus(CW1, CW3, DR4, DRW9). Familial CP in our clinic has an increased frequency of the HLA types DR-2. There is no strong relationship between HLA and etiological factors of CP.We think the defensive mechanism plays the mafor role of developing pancreatitis. Genomic DNA was prepared from peripheral leukocytes and digested with EcoRI.HindIII, BamHI, *and StagI.Southern blot analysis revealed neither a rearrangement nor a gross delection of pancreatic secretory trypsin inhibitor(PSTI) and Reg genomic DNA of affected members of two families. Four exons of PSTI gene amplified by polymerase chain reaction(PCR) from genomic DNA was directly sequenced. One single-base change in the PSTI gene of familial CP was observed. But we have not confirmed this region influenced the synthesis of protein.