The ascending pathophysiology of cholestatic liver disease

Abstract

In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending course of the disease process. The first and early lesions are in “downstream” bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)–mediated toxic injury of the “upstream” liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom‐poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50%‐60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more “tailored” use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium‐dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis–suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti‐inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor‐ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and cholangitis, not for cholestasis in end‐stage disease. These are arguments to consider a step‐wise pathophysiology for these diseases, with therapy adjusted to disease stage. An obstacle in such an approach is that disease stage–defining biomarkers are still lacking. This review is meant to serve as a call to prioritize the development of biomarkers that help to obtain a better stratification of these diseases. (Hepatology 2017;65:722‐738).

Bile Microinfarcts in Cholestasis Are Initiated by Rupture of the Apical Hepatocyte Membrane and Cause Shunting of Bile to Sinusoidal Blood

“…Recently, the concept of an ascending pathophysiology of cholestatic liver disease has been proposed, whereby lesions start in large or small bile ducts followed by the involvement of upstream structures, such as the bile canalicular network and liver parenchyma . Our knowledge of the responses of the biliary tree to cholestasis stems mainly from studies in rodents after bile duct ligation (BDL).…”

“…Our knowledge of the responses of the biliary tree to cholestasis stems mainly from studies in rodents after bile duct ligation (BDL). BDL in mice or rats cannot fully recapitulate human cholestatic liver diseases, such as primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) . A major difference is the total disruption of biliary flux after BDL, which is not the case in PBC or PSC.…”

Characterization of hepatocyte-based in vitro systems for reliable toxicity testing

“…A third type of liver toxicity to be 1 3 tested includes cholestasis. Cholestatic liver injury is the result of a direct deteriorative response and an indirect adaptive response of hepatocytes to various insults, including those caused by drugs (Jansen et al 2017). A common protocol to evoke cholestatic hepatotoxicity in vitro, which can be detected by chromatographic bile acid analysis, is the simultaneous exposure of hepatocyte-based cell culture systems to a cholestatic drug and a concentrated bile acid mixture.…”

Highlight report: adaptations of the biliary tree to cholestasis

“…Recently, Peter Jansen and colleagues have published a comprehensive review article about the pathophysiology of cholestatic liver disease (Jansen et al 2017). One of the central key messages of this article is that cholestatic liver disease typically evolves with anatomically an ascending course, where the early lesions occur 'downstream' in bile ducts, which later leads to 'upstream' bile salt mediated damage of hepatocytes.…”

“…The bile canalicular network represents the most upstream domain of the biliary tract. In cholestasis, canaliculi show increased average diameters and an increase in the frequency of spine-or bleb-like protrusions into hepatocytes (Jansen et al 2017). The causes of these changes are still controversially discussed and range from biochemically induced tight junctional remodeling and altered pericanalicular action to a possible consequence of increased canalicular pressure (Masyuk et al 2001;Das et al 2009;Liu et al 2015 …”