Ischemia and cholestasis: more than (just) the bile ducts!

L iver ischemia and hypoxia can lead to cholestasis through various mechanisms and may present in different clinical scenarios. In general, cholestasis can occur at the level of hepatocytes (hepatocellular cholestasis) or of bile duct epithelial cells (ductular/ductal cholestasis) (Fig. 1). The clinical consequences of hepatocellular and ductular cholestasis may be completely different with considerable variations in the time of onset after the initial insult, disease course and prognosis. Although hepatocellular impairment of bile formation because of alterations in hepatic blood flow and ischemia is in principle fully reversible, ischemic damage to bile duct epithelial cells (cholangiocytes) can lead to a progressive, irreversible cholestatic disease with features of sclerosing cholangitis (ischemic cholangiopathy) (1, 2). In its most severe presentation, hypoxia caused by hepatic artery thrombosis (HAT) may be an important cause of cholestasis after orthotopic liver transplantation (OLT) (1). Liver ischemia may also play a role in cholestasis in critically ill patients on intensive care units and may thus contribute to sepsis/SIRS-associated cholestasis in addition to cytokine-mediated repression of hepatobiliary transport (2). In addition, hemodynamically instable patients often require high doses of catecholamines that lead to vasoconstriction of the splanchnic arteries and thus—together with reduced systemic arterial pressure—reduce hepatic perfusion. Notably, patients with severe sepsis, trauma or burns can develop a rapidly progressive sclerosing cholangitis that has been attributed to ischemia as one of the key pathogenetic mechanisms (2). Chronic respiratory failure caused by chronic pulmonary disease and sleep apnea can also significantly reduce hepatic blood flow and oxygen deliver (3). Hemodynamic alterations during surgery and anesthesia reduce hepatic blood flow and may contribute to “benign” postoperative cholestasis (3). With the exception of HAT and other, even more rare causes of ischemic cholangiopathy (e.g., vasculitis) (1), cholestasis in these scenarios develops mainly in the absence of frank bile duct injury, suggesting underlying functional/hepatocellular mechanisms. A combination of ischemia and hypoxia and reperfusion-related injury has been favored as the underlying mechanism (3, 4), whereas the effects of “pure” ischemia without reperfusion have so far received only little attention in the pathogenesis of cholestasis. In this issue of Transplantation, Hoekstra and co-workers (5) present a mouse model of severe hepatic ischemia with disruption of arterial perfusion through both the hepatic artery (HA) and the peribiliary plexus (PBP), mimicking HAT after OLT. This work sheds more light on the potential pathomechanisms leading to ischemia-induced cholestasis. In the current study, complete loss of both hepatic arterial blood supply caused by disruption of the HA and the PBP resulted in persistent elevation of serum markers of cholestasis and the development of cholangitis within 4 weeks (5). This is in contrast to the consequences of hepatic ischemia in rats, where biochemical markers of cholestasis normalize within 6 weeks after ischemia (6, 7), indicating that mice may better resemble the human situation. As a potential key mechanism, Hoekstra et al. (5) propose early hepatocellular ATP depletion as a consequence of limited metabolic capacity, leading to impaired bile formation, which heavily depends on proper function of ATP-binding cassette transporters (2, 8, 9). In addition, expression of the major bile acid transporters (the basolateral sodium taurocholate cotransporter [Ntcp] and the canalicular bile-salt export pump [Bsep] mediating the rate limiting step in bile acid secretion) was reduced (5). Hepatocellular retention of toxic bile acids may further augment hepatocellular liver injury and could perpetuate the initial inflammatory response by stimulating production of proinflammatory cytokines (i.e., TNFand IL-1 ) (10). Prolonged inflammation could in turn further repress the expression of transport systems, creating a vicious cycle of inflammation and cholestasis (2, 11). The current study by Hoekstra et al. (5) is notable, because in their model, ischemia-induced liver injury and progressive cholestasis developed without reperfusion, which has so far been considered a critical second hit in development of ischemiainduced cholestasis (3, 12). However, some of the key mechanisms may be similar. Ischemia-induced oxidative stress and formation of reactive oxygen species may contribute to impairment of bile formation by repressing transporter expression (Fig. 1) (5–7). In addition to transcriptional changes, retrieval of transporters from the canalicular membrane may also contribute to cholestasis (Fig. 1) (8, 13, 14). The appearance of bile duct alterations, which mark the transition from a potentially reversible disease state into a fixed irreversible stage, is of utmost concern for clinicians. The biliary tract is considered to be the Achilles’ heel in vascular liver supply because of its exclusive dependence on oxygen supply through the HA and the connected PBP (Fig. 1). Cholangiocytes display morphological signs of cellular injury and markers of hypoxia as early as 4 hr after the onset of ischemic injury (6, 7) and seem to be more susceptible to ischemia and hypoxia than hepatocytes (4). In addition, an imbalance between toxic biliary bile acids and biliary phospholipids normally protecting the bile ducts from toxicity of high bile acid concentrations in the millimolar range in bile may play a key role (Fig. 1) (15). This “toxic bile” concept is underlined by the development of sclerosing cholangitis in mice lacking the canalicular phospholipid flippase multidrugSupported by grant P18613-B05 (M.T.) from the Austrian Science Foundation. Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Graz, Austria. Address correspondence to: Michael Trauner, M.D., Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine, Medical University Graz, Auenbruggerplatz 15, A-8036 Graz, Austria. E-mail: michael.trauner@meduni-graz.at Received 18 January 2008. Accepted 25 January 2008. Copyright © 2008 by Lippincott Williams & Wilkins ISSN 0041-1337/08/8508-1083 DOI: 10.1097/TP.0b013e31816b2393