Review: pathogenesis of gallstones
Review: pathogenesis of gallstones
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DOI：
10.1046/j.1365-2036.2000.014s2039.x
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发表时间：
2000-05-01
影响因子：
7.6
通讯作者：
Dowling, RH
中科院分区：
文献类型：
--
作者：
Dowling, RH
本文旨在综述胆固醇含量高的胆囊结石（GBS）发病机制的某些方面，重点是胆汁胆固醇饱和、胆固醇微晶成核、胆囊内胆汁淤积的最新进展，特别是肠道转运和脱氧胆酸（DCA）代谢改变在GBS发生中的作用。最近的发展包括在人类和动物中的证据，即胆汁脂质分泌受遗传控制。因此，在小鼠中，md-2基因和在人类中的MDR-3基因编码小管蛋白，其充当将磷脂从小管膜的内部半小叶转运到外部半小叶的“翻转酶”。如果没有这种基因，实际上没有磷脂或胆固醇分泌到胆汁中。此外，当具有“结石基因”的近交系小鼠被喂食致石饮食时，它们变得对高速率的GBS形成敏感。胆固醇微晶从过饱和胆汁中沉淀/成核仍然是胆结石形成的关键步骤。研究这种现象的方法现在已经从最初的"成核时间“改进为胆固醇出现/检测时间的测量和晶体生长测定。此外，最近的研究结果表明，除了经典的菱形一水合物晶体外，胆固醇还可以瞬时结晶为无水胆固醇的针状、螺旋形和管状晶体。现在已经定义了一个长长的促进剂列表和一个较短的抑制剂列表。在许多情况下，人体GB停滞与胆石形成风险增加相关-包括长期接受奥曲肽（OT）治疗的肢端肥大症患者的医源性结石形成。然而，除了GB淤滞，OT治疗的患者都具有胆固醇过饱和的“坏”胆汁，囊泡中具有过量的胆固醇，快速的微晶乳化时间和胆汁中DCA百分比的两倍增加。DCA比例的增加似乎是由于OT诱导的大肠通过时间（LBTT）延长。因此，LBTT与（i）血清中DCA的百分比;（ii）DCA池大小;和（III）DCA输入或“合成”速率线性相关。此外，肠道促动力剂西沙必利可以对抗OT对肠道运输的不利影响，并使血清/胆汁中DCA的百分比“正常化”。自发性胆结石病患者的LBTT时间延长，结肠革兰氏阳性厌氧菌增多，胆汁酸代谢酶增加和更高与无结石对照组相比，结肠内pH值更高。总之，这些变化导致DCA形成、溶解和吸收增加。因此，除了“致石性肝脏”和“有罪的胆囊”之外，现在必须将“惰性肠”添加到胆固醇结石形成的罪魁祸首列表中。
The aim of this article is to review selected aspects of the pathogenesis of cholesterol-rich, gall-bladder stones (GBS) - with emphasis on recent developments in biliary cholesterol saturation, cholesterol microcrystal nucleation, statis within the gall-bladder and, particularly, on the roles of intestinal transit and altered deoxycholic acid (DCA) metabolism, in GBS development.In biliary cholesterol secretion, transport and saturation, recent developments include evidence in humans and animals, that bile lipid secretion is under genetic control. Thus in mice the md-2 gene, and in humans the MDR-3 gene, encodes for a canalicular protein that acts as a' flippase' transporting phospholipids from the inner to the outer hemi-leaflet of the canalicular membrane. In the absence of this gene, there is virtually no phospholipid or cholesterol secretion into bile. Furthermore, when inbred strains of mice that have 'lith genes' are fed a lithogenic diet, they become susceptible to high rates of GBS formation.The precipitation/nucleation of cholesterol microcrystals from supersaturated bile remains a critical step in gallstone formation. methods of studying this phenomenon have now been refined from the original nucleation time' to measurement of cholesterol appearance/detection times, and crystal growth assays. Furthermore, the results of recent studies indicate that, in addition to classical Rhomboid-shape monohydrate crystals, cholesterol can also crystallize, transiently, as needle-, spiral- and tubule-shaped crystals of anhydrous cholesterol. A lengthy list of promoters, and a shorter list of inhibitors, has now been defined.There are: many situations where GB stasis in humans is associated with an increased risk of gallstone formation - including iatrogenic stone formation in acromegalic patients treated chronically with octreotide (OT). As well as GB stasis, however, OT-treated patients all have 'bad' bile which is supersaturated with cholesterol, has excess cholesterol in vesicles, rapid microcrystal mulceation times and a two-fold increase in the percentage DCA in bile. This increase in the proportion of DCA seems to be due to OT-induced prolongation of large bowel transit time (LBTT). Thus LBTT is linearly related to (i) the percentage of DCA in serum; (ii) the DCA pool size; and (III) the DCA input or 'synthesis' rate. Furthermore, the intestinal prokinetic, cisapride, counters the adverse effects of OT on intestinal transit, and 'normalizes' the percentage of DCA in serum/bile.Patients with spontaneous gallstone disease also have prolonged LBTTs, more colonic Gram-positive anaerobes, increased bile acid metabolizing enzymes and higher intracolonic pH values, than stone-free controls. Together, these changes lead to increased DCA formation, solubilization and absorption. Thus, in addition to the 'lithogenic liver' and 'guilty gall-bladder' one must now add the 'indolent intestine' to the list of culprits in cholesterol gallstone formation.