Circulating bile acids predict outcome in critically ill patients

Jaundice and cholestatic liver dysfunction are found in 10–20% of critically ill patients and are associated with markedly increased mortality [1‐6]. Cholestasis in critically ill patients is associated with the presence of shock, sepsis, major surgery, hepatotoxicity of drugs and parenteral nutrition [4, 6‐8]. While no universal definition of cholestasis has been established [1, 6, 7, 9, 10], the complexity of cholestasis, characterized by impaired bile formation and flow and subsequent bile acid (BA) retention, may not be sufficiently reflected by bilirubin [6, 11]. Although hyperbilirubinemia and accumulation of serum BAs are frequent findings in critically ill patients, underlying molecular pathways and clinical implications are still poorly understood. The clinical impact of serum BAs in critically ill patients has been assessed in a few studies focusing on sepsis [2, 6, 12, 13].

Cholestasis and sepsis are closely connected as expression of pro-inflammatory cytokines results in impaired bile secretion [1, 3, 13‐15]. BAs are primarily synthesized in the liver out of cholesterol undergoing enterohepatic circulation (biliary excretion/ileal reabsorption) and then converted to secondary BAs by the gut microbiota [15‐24] BA’s metabolic (regulation of lipid and energy homeostasis) and signalling properties are regulated via a complex network of nuclear receptors (NRs) such farnesoid-X-receptor (FXR) and G-protein-coupled BA receptor (TGR5) [17, 22‐24]. BAs are directly vasoactive mediators and furthermore are capable of stimulating hepatocytes’ production of proinflammatory cytokines [25‐29]. Furthermore, BAs directly influence cardiac function (myocardial contractility and relaxation) [30, 31]. Whether BA retention is a distinct pathophysiological entity or a biochemical epiphenomenon of severity of critical illness or even a compensatory mechanism with potential beneficial (e.g. metabolic or even anti-inflammatory) effects remains unclear [6].

Aim of this study was to assess the clinical relevance of circulating BAs in a large cohort of critically ill patients.

Early hepatic dysfunction is a frequent finding in critically ill patients [6, 7]. Prolonged length of stay as well as worse outcome has been reported to be strongly associated with cholestatic impairment [1, 3, 5, 6]. However, there is lack of data regarding the clinical relevance of early hepatic dysfunction by means of altered serum BA levels and composition in different disease entities in critically patients. Therefore, we aimed to describe the clinical impact of circulating serum BAs and individual composition in a cohort of critically ill patients, mainly suffering from cardiogenic and septic shock.

Our results demonstrate an elevation of individual as well as TBAs in a heterogeneous group of critically ill patients compared to controls. Notably, the highest levels of BAs were found in patients with septic shock. In patients with cardio-circulatory disorders, serum BA levels were still significantly higher than in patients following cardiothoracic surgery or controls. Severity of underlying disease did not differ in patients with septic or cardiogenic shock or those following surgery or others. Potentially toxic conjugates of unconjugated primary BAs CL and CDC were highest in accordance with previous reports [2]. The lack of difference of primary BAs (e.g. CDC) in between groups may reflect the organisms’ ability of enhanced conjugation of probably toxic BAs under condition of critical illness. However, both increasing conjugated and unconjugated BAs during critical illness have been reported [3, 6]. BAs are known for cytotoxic effects, in particular hydrophobic BAs are capable of inducing irreversible cell damage [41]. A change in hydrophilic-hydrophobic balance towards hydrophobicity in ICU patients compared to controls may be assumed. In our cohort, highly hydrophobic LC and DC were significantly higher in patients with cardiogenic shock than in controls. Best correlation of BAs and severity of disease (SAPS2 score) was seen in glycine conjugates of toxic LC. Additionally, we observed a significant correlation of GC and GDC with arterial serum lactate levels.

BAs correlated with markers of inflammation like C-reactive protein, leucocytes and fibrinogen. Hydrophobic taurine conjugates of CDC were more than 40-fold higher in blood stream infection compared to pneumonia. The highest TBA levels were seen in urosepsis, followed by catheter and blood stream infection and pneumonia. Common pathogens of urosepsis as well as hospital-acquired pneumonia are gram-negative bacteria (e.g. Escherichia coli, Pseudomonas aeruginosa, Haemophilus influenzae) which are known to predominantly repress hepatobiliary transporter expression and subsequently BA retention in vivo [13, 15, 42, 43]. BAs are important signalling molecules interacting between liver, bile and gut and are involved in lipid and energy homeostasis [17]. They are a major regulator of the gut microbiota and directly interact with gut bacteria. It has been suggested that intestinal microorganisms benefit from metabolizing BAs as they acquire glycine/taurine [44]. Elevated intake of BAs results in changes of the gut microbiota by means of inhibition of Actinobacteria and Bacteroidetes [22, 44]. Altered gut integrity due to increased intestinal permeability and bacterial translocation represent important triggers of sepsis and sepsis-related organ dysfunction [45]. Serum BA levels are able to directly trigger inflammatory processes via cytokine expression [25‐27]. Conversely, BA also have anti-inflammatory and immunosuppressive properties mediated by FXR and TGR5 via modulating anti-inflammatory gene expression [17, 46, 47] Thus, BAs may have both pro- and anti-inflammatory actions depending on the time course and concentrations of serum BA levels during sepsis [48].

Sepsis-related volume disturbances and subsequent hemodynamic changes seem to be relevant triggers of multifactorial genesis of renal failure in critically ill patients with cholestatic dysfunction [5]. Interestingly, we found a clear association of serum BA retention and need of RRT as well as serum markers of kidney dysfunction. Oxidative stress has been postulated as central mechanism inducing cholestasis associated renal impairment [49]. Recently, BAs have been implicated in kidney injury due to longstanding jaundice. Cholemic nephropathy represents typical histopathological alterations including tubular epithelial cell injury and intratubular cast formation in patients with cholestasis [50, 51]. In addition, solubility of BAs is increased in acidic milieu such as metabolic acidosis, which may reflect another factor for urinary cast formation and interstitial tubular damage [52].

BAs have directly vasoactive properties, inducing peripheral vasodilation via relaxing smooth muscle cells. Furthermore, alterations of BA metabolism have been found in cardiac disease and heart failure [30, 31, 53]. Recently, G-protein-coupled BA receptor-1 has been identified as central pathway in BA-mediated hemodynamic alterations [28, 29]. We observed a significant correlation of TC and TCDC with arterial blood pressure in our cohort. Valvular heart disease and subsequent congestive heart failure, chronic cardiac disorders, frequently lead to backward right ventricular heart failure with consecutive congestive hepatopathy and concomitant jaundice [5, 54]. Bilirubin and low serum albumin levels have been reported to be associated with elevated mortality rates in patients hospitalized for heart failure [55]. BAs impact on cardiac function as they modulate myocardial contractility and relaxation [30, 31]. They reduce duration of ventricular myocytes’ action potential and have proarrhythmogenic properties [30]. In our cohort, TBAs were significantly higher critically ill patients with cardiogenic shock compared to surgical patients and controls. Highest levels of serum BAs were seen in valvular heart disease and decompensated heart failure. Individual and TBAs correlated significantly with pro-BNP levels.

Serum BAs correlated with bilirubin in our heterogenous collective of critically ill patients. Strongest correlation was seen in septic patients, which even increased during course of time. The underlying mechanism of hyperbilirubinemia in critically ill patients is not fully understood. Whether cholestasis during critical illness is merely a biological epiphenomenon of the failing organ or even has protective effects remains unclear [2, 6, 56]. However, several factors influence bilirubin levels, such as infections of the liver, transfusion of red blood cells and/or hemolysis [6]. Therefore, bilirubin may not represent the ideal parameter for assessing hepatic organ dysfunction in the ICU [6]. In our cohort, both BAs and bilirubin were elevated in patients that died within the first 28 days. However, serum BAs showed better predictive properties than bilirubin.

Our data demonstrated that an early increase of circulating BAs in a heterogeneous collective of critically ill patients is associated with increased 28-day mortality. TBAs predicted short-term mortality independently of serum bilirubin levels and severity of critical illness. BA’s predictive properties seem to be higher than bilirubin’s in accordance with another recent publication [3]. Best prediction of mortality was observed in patients with septic shock. As TBAs can easily be measured in standard hospital laboratories, available at manageable costs BAs could represent an early non-invasive marker for predicting outcome and serve as a new tool for early risk stratification in critically ill patients.

Apart from its prognostic implications, future studies should clarify if modulation of BA levels has clinical implications on new onset of organ failure and outcome. Advanced dialysis systems like liver support devices are capable of eliminating albumin bound substances (such as serum BAs) [57, 58]. Furthermore, several drugs can modify BA levels and signalling. BA sequestrants such as non-absorbed resins lower BA levels via binding and removing them from enterohepatic circulation [16]. Intestinal interception in BA transport and signalling may prevent systemic side effects while restoring BA homeostasis and gut integrity [47, 59, 60]. Future studies should clarify whether device-based or medication-based BA modifications including ligands for FXR and TGR5 may have an impact on clinical course and outcome of critically ill patients.

To conclude, our study demonstrates that circulating individual and total BAs are elevated by various degrees in different shock conditions. BAs represent an early predictor of short-term survival in a mixed cohort of ICU patients and may serve as a novel marker for early risk stratification in critically ill patients. Future studies should elucidate whether modulating BA metabolism or elimination of BAs by extracorporeal devices influences clinical course and outcome.