January 18, 2016

The Significance of Hippocratic Yellow Bile in the Critically Ill 

Physicians since the time of Hippocrates have understood the poor prognosis of a patient with an accumulation of Yellow Bile. While the pathophysiology of acute and chronic liver failure is relatively well documented, the aetiology of biochemical changes frequently observed by intensivists in their patients that denote hepatic dysfunction in patients without overt liver failure remains the subject of investigation. Elevations of liver biochemistry are doubtless detrimental to the critically ill patient’s prognosis (1). The rare review of this area by Jenniskens et al in this month’s ICM is a worthwhile read as it focuses on the integration clinical and laboratory evidence on ‘cholestatic’ liver dysfunction (CLD) (2). CLD in the critically ill usually occurs in the absence of mechanical obstruction of the biliary tree in the critically ill and instead reflects changes in the metabolic and excretory pathway of bile. The authors clearly describe the ‘multiple hepatic insults’ seen in critically ill adults from sepsis, trauma, medication, parenteral nutrition and glycaemic dysregulation that may contribute to CLD.

Having reviewed hepatocellular anatomy and bile acid metabolism in health, the article pieces together what is known of the dysregulation that occurs in critically illness. The liver is a challenging organ to study in critical illness due to the difficulties of safely obtaining tissue samples and the relative paucity of practical radiological techniques to assess function. Particularly fascinating are the insights gained from human agonal serum and immediate post-mortem hepatic tissue which indicated continued bile acid formation and loss of the usual feedback inhibition, as well as altered regulation of several bile membrane transporters. The result is a redirection of bile acids into the systemic circulation. While animal models of bile and drug transport and metabolism can provide insights into the effects of critical illness on these pathways, the specie-specific variation in transporter and cytochrome regulation, particularly in response to inflammatory stimuli, may limit their applicability to the critically ill human(3).  

The review stresses the inadequacies of current ‘liver function tests’. Future metabolomic research may improve the definition of liver dysfunction in critical illness. In a particularly original section, the authors speculate on whether the biochemical changes in critical care cholestatic liver disease could be a protective rather than maladaptive response. Bilirubin may have a number of redox and anti-inflammatory roles as well as promoting insulin sensitivity.  

This thorough review of the existing literature raises many more questions and a number of priorities for future research in this challenging area. 

This article review has been prepared and submitted by Katie Lane on behalf of the NEXT Committee.


1.  Kramer L, Jordan B, Druml W, Bauer P, Metnitz PGH, Austrian Epidemiologic Study on Intensive Care ASDI Study Group (2007) Incidence and prognosis of early hepatic dysfunction in critically ill patients—a prospective multicenter study. Crit Care Med 35:1099–1104.

2.  Jenniskens et al. Cholestatic liver (dys)function during sepsis and other critical illnesses. Intensive Care Medicine. (January 2016) 42:16 – 27

3.  Lane K, Dixon JJ, MacPhee I a M, Philips BJ. Renohepatic crosstalk: does acute kidney injury cause liver dysfunction? Nephrol Dial Transplant. 2013;28(7):1634-1647.


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