Cholestatic liver (dys)function during sepsis and other critical illnesses

In ICU patients, abnormal liver tests are common. Markers of cholestasis are associated with adverse outcome. Research has focused on the possibility that mild hyperbilirubinemia, instead of indicating inadvertent cholestasis, may be adaptive and beneficial. These new insights are reviewed and integrated in the state-of-the-art knowledge on hepatobiliary alterations during sepsis and other critical illnesses. Relevant publications were searched in Medline with search terms bile, bile acids, cholestasis, critical illness, intensive care, sepsis, alone or in combination. Studies have shown that bilirubin, but also bile acids, the main active constitutes of bile, are increased in plasma of patients with critical illnesses. In particular the conjugated fractions of bilirubin and bile acids are high, indicating that during critical illness the liver is capable of converting these molecules to less toxic forms. In human liver biopsies of prolonged critically ill patients, expression of bile acid excretion pumps towards the bile canaliculi was lower, while alternative transporters towards the systemic circulation were upregulated. Remarkably, in the presence of increased circulating bile acids, expression of enzymes controlling synthesis of bile acids was not suppressed. This suggested loss of feedback inhibition of bile acids synthesis, possibly explained by the observed cytoplasmic retention of the nuclear FXR/RXR heterodimer. As macronutrient restriction during acute critical illness, an intervention that improved outcome, was found to further increase plasma bilirubin while reducing other markers of cholestasis, a potentially protective role of hyperbilirubinemia was suggested. The increase in circulating levels of conjugated bile acids and bilirubin in response to acute sepsis/critical illnesses may not necessarily point to cholestasis as a pathophysiological entity. Instead it may be the result of an adaptively altered bile acid production and transport back towards the systemic circulation. How these changes could be beneficial for survival should be further investigated.