Canal of Hering loss is an initiating step for primary biliary cholangitis (PBC): A hypothesis
Canal of Hering loss is an initiating step for primary biliary cholangitis (PBC): A hypothesis
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DOI：
10.1016/j.mehy.2020.109680
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发表时间：
2020-07-01
影响因子：
4.7
通讯作者：
Quaglia, Alberto
中科院分区：
文献类型：
--
作者：
Theise, Neil D.;Crawford, James M.;Quaglia, Alberto
经过几十年的研究，PBC的起源和发病特征仍不清楚。然而，最近的论文表明，原发性胆道胆管炎（PBC）患者肝活检标本中最早的组织学改变是Hering管丢失（CoH）。我们认为，在明显炎症或胆管损伤证据之前，CoH丢失可能是PBC的早期，甚至可能是初始病变。作为炎症或毒性损伤的潜在靶标，CoH丢失可能是导致导管损伤和丢失及其后遗症的一系列事件的始发而非后续。毒素可能是外源性的，如环境毒素或药物暴露，也可能是内源性的，由CoH上游的小管胆汁转运体的遗传或表观遗传改变引起。反过来，这一假设表明，CoH的损失会导致胆汁流量和成分的改变，对下游胆管有害，因为胆汁成分不能被正常的CoH生理功能调节，或者因为在缺乏CoH的情况下，进入胆道树的管状液体被破坏，干扰了对胆管完整性重要的可溶性营养因子。无论导致CoH丢失的致病机制如何，只有在这种丢失之后，PBC的特征性诊断结果才会变得明显：下游小叶间胆管和小叶下胆管受损。在某种程度上，CoH丢失的因果机制可以确定，临床鉴定（如通过早期识别CoH丢失）和干预（取决于诱发原因）可能为治疗这种神秘疾病提供希望。
The origin and initiating features of PBC remain obscure despite decades of study. However, recent papers have demonstrated loss of canals of Hering (CoH) to be the earliest histologic change in liver biopsy specimens from patients with primary biliary cholangitis (PBC). We posit that CoH loss prior to significant inflammation or evidence of bile duct injury might be a very early, perhaps even an initiating lesion of PBC. As a potential target of inflammatory or toxic injury, CoH loss may initiate rather than follow the cascade of events leading to duct injury and loss and their sequelae. Toxins may be exogenous in origin, such as environmental toxins or drug exposures, or endogenous, resulting from genetic or epigenetic alterations in canalicular bile transporters upstream from the CoH. In turn, this hypothesis suggests that loss of CoH would lead to altered bile flow and composition injurious to downstream bile ducts, because bile composition has not been modulated by normal CoH physiologic functions or because, in the absence of CoH, canalicular fluid flow into the biliary tree is disrupted interfering with soluble trophic factors important for bile duct integrity. Regardless of the pathogenic mechanism causing CoH loss, only following such loss would the characteristic diagnostic findings of PBC become evident: damage to downstream interlobular and sub-lobular bile ducts. To the extent that the causal mechanisms for CoH loss can be identified, clinical identification (as through early identification of CoH loss) and intervention (depending on the inciting cause) may offer promise for treatment of this enigmatic disease.