Shades of yellow: Monitoring nutritional needs and hepatobiliary function in the critically ill
Authors: Michael Bauer, Michael Kiehntopf
Journal: Hepatology (2014)

Ever since the seminal studies by Wilmore and Dudrick in the late 1960s,1, 2 areas of uncertainty remained in identifying those patients who would benefit from specialized nutrition support and most notably supplemental parenteral nutrition to attain a prescribed caloric goal. Both hyperalimentation as well as malnutrition, either preexisting or developing during critical illness and the associated state of hypercatabolism, are undoubtedly associated with a poor outcome. Fundamental questions, such as optimal timing of enteral or parenteral formulas alone or in combination, and composition of formulations regarding relative amounts of carbohydrates, fat, and protein remain unknown or controversial even for patients without comorbidities. While there is widespread agreement that "trophic" feeding (∼400 kcal/day by way of the enteric route) is beneficial, the need for "full" caloric support (∼1,300 kcal/day or 75% of daily requirement) that frequently will only be achieved if parenteral nutrition (PN) is used to close the gap between tolerated enteral feeding and the daily caloric goal remains controversial: More specifically, several recent randomized controlled trials (RCTs) would support the notion that limited nutrition by way of the enteral route is associated with less vomiting and gastric residual volumes without a negative impact on morbidity, in particular the need for mechanical ventilation and mortality,3, 4 while observational trials suggested an inverse relationship between the amount of energy and protein delivered and the rate of intensive care unit (ICU)-acquired infections.5 Achieving the caloric goal by total (T)PN should be postponed or even be restricted to anatomical abnormalities, as TPN might, among other side effects, lead to hepatocellular steatosis and cholestatic liver dysfunction.6 In this issue of Hepatology, Vanwijngarden et al.7 report the results of a preplanned subanalysis on hepatobiliary outcome parameters of the large (4,640 patients), multicenter, randomized EPaNIC trial that addressed the fundamental uncertainty regarding caloric goals and parenteral supplementation to achieve these goals that is reflected in the discrepancy between American and European guidelines. Delaying PN beyond day 7 (according to the American standards) was associated with faster recovery and fewer complications overall, as compared with early initiation.8 While bilirubin levels were paradoxically higher in the late-PN group, the other conventional indicators of parenchymal and hepatobiliary injury (gamma-glutamyl transpeptidase [GGT], alkaline phosphatase [ALP], and alanine aminotransferase [ALT]) were lower, while unconjugated and glycine/taurine-conjugated primary bile acids (BAs) increased similarly over time in both groups. The parental EPaNIC trial has been scrutinized regarding need for parenteral supplementation, composition of formulas, glycemic control, included patient populations, and timing of initiation of parenteral caloric support.9 Specifically, approximately half of the patients were extubated at day 2 and discharged at day 4 and more than 60% of the patients were cardiac surgery patients. Thus, the severity of illness including markers of hepatobiliary dysfunction of the studied patient population was relatively mild. Nevertheless, this study raises fundamental questions regarding the monitoring of metabolism in the critically ill and the interaction of critical illness, nutritional strategies, and hepatobiliary function. Strategies of high-dimensional biology to study the integrated response of the liver to critical illness, most notably severe infection and sepsis, suggest that a reprogramming of a wide range of metabolic functions occurs in parallel with a severity-dependent disruption of biotransformation and canalicular transport resulting in excretory failure.10 In parallel, an even less well-studied gastrointestinal impairment seems to occur in these patients, in which lipid malabsorption might persist despite recovery of motility and glucose resorption.11 Systemic and local inflammation as triggering events of the acute phase response is characterized by activation of nonparenchymal (immune) cells and production of proinflammatory cytokines with ensuing development of hyperglycemia and peripheral insulin resistance. Inflammasomes are intracellular multiprotein complexes expressed in both parenchymal and nonparenchymal cells of the liver that in response to cellular danger signals activate caspase-1, and release interleukin (IL)-1β and IL-18. The importance of the inflammasome is increasingly recognized as central to the understanding of liver dysfunction in systemic inflammation, infection, and sepsis. Moreover, this multiprotein oligomeric innate immune complex can be activated specifically in response to bacterial pore-forming toxins, such as α-toxin of Staphylococcus aureus or pneumolysin of Pneumococci to initiate activation of sterol regulatory element binding proteins (SREBPs) linking caspase-1 to lipid metabolic pathways.12 Activation of SREBPs by pneumolysin induces an ensuing substantial increase in plasma cholesterol, a precursor of BAs generated by cholesterol oxidation, by way of remote induction of the pathway in the liver.13 In addition to their role in lipid absorption and cholesterol homeostasis, BAs function as signaling molecules through binding to receptors such as the farnesoid X receptor (FXR). The ensuing activation of downstream signaling pathways is known to impact hepatic lipid, glucose, and energy homeostasis in health and the metabolic syndrome that mimics many of the facets of metabolic derangement in the critically ill.14 Another aspect of the inflammatory response, i.e., formation of reactive oxygen species, triggers heme oxygenase activity in the liver, which catalyzes oxidative cleavage of the α-mesocarbon of heme, yielding equimolar amounts of biliverdin, iron, and carbon monoxide. Biliverdin will subsequently be processed to form bilirubin. Fasting by itself may induce heme oxygenase-1,15 which is linked to induction of autophagy, a central effector mechanism of hepatocellular stress tolerance.16 In an additional subanalysis from the EPaNIC trial, the authors recently reported that early supplementation of failing enteral nutrition with (T)PN impaired autophagy at least in skeletal muscle biopsies, providing evidence for a role of autophagy as a putative mechanism for protection also in the hepatobiliary system of these patients.17 Autophagy is now recognized as a key adaptive stress response which negatively regulates inflammasome activation18 (Fig. 1). These observations underline the tight relationship of inflammation, metabolism, and hepatobiliary function in the critically ill and might underlie the observed differences between early and late PN regarding plasma bilirubin, indicators of cholestastic injury, and sludge formation observed by Vanwijngarden et al. Albeit the observed increase in plasma bilirubin with calorie restriction in the study is modest, it might, along with the "J"-shaped mortality curve depending on the bilirubin plasma level, serve to extend the experimental concept of heme oxygenase and its metabolites as central cellular weapons of hepatocellular defense to the clinical setting.19 Clinicians caring for the critically ill are dealing with these complex metabolic states and have to base their therapeutic decisions on guidelines and a handful of metabolites, such as glucose, lactate, BUN, and the lipid profile that can currently be measured in routine care. A recent survey of ∼200 ICUs across the UK revealed that in less than 20% of the units was a nutrition support team available.20 Energy expenditure is rarely measured in the ICU and energy requirements are based on calculations using, e.g., the Harris-Benedict formula. As a result, energy prescriptions rarely reflect the actual needs of patients, a serious concern in particular in long-term ventilated critically ill patients.21 In a more general way, the concept of "individualized" or "personalized" care, implying stratification of the patient based on a better assessment of the complex disease process, is challenging but holds great promise for the critically ill. Monitoring metabolism in a more comprehensive way applying mass spectrometry to assess the "metabolome," i.e., "metabolomics" is currently tiptoeing into clinical routine.22 This technique can be performed in an "untargeted" approach, or to monitor specific groups of analytes, such as the unconjugated and glycine/taurine-conjugated primary bile acids, as in the study by Vanwijngarden et al. While traditionally bilirubin serves exclusively to monitor excretory liver function in the ICU, e.g., in the most widely used scoring system for multiple organ dysfunction, the SOFA score,23 emerging evidence suggests that bile acids might indicate liver dysfunction with higher sensitivity and specificity,10 or at least be widely independently increased from bilirubin.7 In any case, these modest increases in bilirubin, even considering the imprecision of current clinical methods to assess minute changes, can be associated with pronounced impairment of phase I and II metabolism,10 which is of concern in these patients.24 A broader assessment of metabolism and the metabolome will likely challenge the preconceived notion of liver dysfunction reflecting a rather late and rare event in the ICU and might be a suitable tool to better monitor hepatobiliary function as well as to personalize metabolic needs and nutritional support in the critically ill. Michael Bauer, M.D.1,2 Michael Kiehntopf, M.D.1,3 1Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany 2Department of Anesthesiology and Critical Care Therapy, Jena University Hospital, Jena, Germany 3Department of Clinical Chemistry & Laboratory Medicine, Jena University Hospital, Jena, Germany