Impact of Parenteral Nutrition Versus Fasting on Hepatic Bile Acid Production and Transport in a Rabbit Model of Prolonged Critical Illness

Cholestatic liver dysfunction frequently occurs during critical illness. Administration of parenteral nutrition (PN) is thought to aggravate this. Underlying mechanisms are not clear.status: publishe

Reduced Cortisol Metabolism during Critical Illness

Critical illness is often accompanied by hypercortisolemia, which has been attributed to stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, low corticotropin levels have also been reported in critically ill patients, which may be due to reduced cortisol metabolism.status: publishe

Pathophysiology of cholestatic liver dysfunction during critical illness

gmeyfr0 12.00 Up to 20% of the patients in the intensivecare unit develop cholestatic liver dysfunction (CLD), which has beenassociated with an increased risk of mortality. Cholestasis can be defined as adecrease in bile flow due to either obstruction of bile flow through mechanicalobstruction of the hepatic bile ducts or to an inability of the hepatocyte tosecrete bile into thebile duct. Mechanical obstruction of the extrahepaticbile duct is easily and robustly diagnosed by ultrasonography, but is only arare cause of CLD in critically ill patients. In contrast, CLD during criticalillness is predominantly due to intrahepatic non-obstructive cholestasis,leading to an intracellular accumulation of bilirubin and bile acids. Althoughincreased concentrations of bile acids inside the hepatocytes are presumed toinduce cholestatic liver damage, the molecular and biochemical changesunderlying CLD are poorly characterized and clear diagnostic criteria arelacking. The most widely used used definition of CLD in clinical practice is ahyperbilirubinemia above 3 mg/dL. However, as a causal link betweenhyperbilirubinemia and worseoutcome is missing, it may even be a biochemicalepiphenomenon. Furthermore, hyperbilirubinemia might represent an adaptiveresponse, as bilirubin can act as an endogenous anti-oxidant and may counteractthe pro-oxidative effects of BA. Additionally, the reliability ofhyperbilirubinemia as a marker of cholestasis in critically ill patients may bequestionable, since there are many factors that can influence the levels ofbilirubin. In this thesis, we therefore aimed atfurther understanding the cholestatic changes at biochemical and molecularlevel during critical illness. The central hypothesis of this doctoral researchproject states that cholestasis , defined as hyperbilirubinemia in the earlyphase of critical illness is brought about by changes in bile acid synthesisand transport and could be a protective response of the liver. As parenteralnutrition (PN) is assumed to aggravate both CLD and biliary sludge formation,we further postulate that parenteral nutrition could modify this protective cholestatic response. EN-US" lang="EN-US">Our findings indicate that cholestasis in critical illness is broughtabout by changes in the hepato-billiary transport system. Critical illnessinduces an immediate increase in circulating conjugated bile acids andbilirubin, apparently brought aboutby a reversal of normal bile acid transportto the blood. The hepatocyte appears to switch off the nuclear bile acidsensors in order to increase circulating bile acids. Avoiding the need for the adaptive response in the liver may be possible by modifying risk factors for developmentof ICU cholestasis , such as parenteral nutrition. We observed that nutrientrestriction during critical illness lowered hepatocyt lysis (AST and ALT) in rabbitsand cholestasis (GGT and ALP) in human patients. Furthermore, nutrientrestriction also reduced the incidence of biliary sludge. In contrast, bilirubin in human patients andconjugated bile acids in rabbits were further increased by nutrientrestriction. Reversal of the hepato-billiary transport system seemsto drive thesebiochemical changes during fasting. These observations strengthen ourhypothesis that early mild hyperbilirubinemia may bea protective response ofthe liver and does not necessarily reflect cholestasis. Nevertheless, only aninterventional study, in which circulating levels of bilirubin are activelymanipulated, can answer whether mild hyperbilirubinemia truly improvespatient-centered outcome during critical illness. 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UnhideWhenUsed="false" Name="Colorful Grid Accent 6"/> UnhideWhenUsed="false" QFormat="true" Name="Subtle Emphasis"/> UnhideWhenUsed="false" QFormat="true" Name="Intense Emphasis"/> UnhideWhenUsed="false" QFormat="true" Name="Subtle Reference"/> UnhideWhenUsed="false" QFormat="true" Name="Intense Reference"/> UnhideWhenUsed="false" QFormat="true" Name="Book Title"/> /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0cm5.4pt 0cm 5.4pt; mso-para-margin-top:0cm; mso-para-margin-right:0cm; mso-para-margin-bottom:10.0pt; mso-para-margin-left:0cm; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New 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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.status: publishe

Contribution of nutritional deficit to the pathogenesis of the nonthyroidal illness syndrome in critical illness: a rabbit model study

Both starvation and critical illness are hallmarked by changes in circulating thyroid hormone parameters with typically low T(3) concentrations in the absence of elevated TSH. This constellation is labeled nonthyroidal illness (NTI). Because critical illness is often accompanied by anorexia and a failing gastrointestinal tract, the NTI of critical illness may be confounded by nutrient deficiency. In an experimental study performed in a rabbit model, we investigated the impact of nutritional deficit on the NTI of sustained critical illness. Critically ill rabbits were randomly allocated to parenteral nutrition (moderate dose 270 kcal/d) initiated on the day after injury and continued until d 7 of illness or to infusing a similar volume of dextrose 1.4% (14 kcal/d). With early parenteral nutrition during illness, the decrease in serum T(3) observed with fasting was reversed, whereas the fall in T(4) was not significantly affected. The rise in T(3) with parenteral nutrition paralleled an increase of liver and kidney type-1 and a decrease of liver and kidney type-3 deiodinase activity and an increase in circulating and central leptin. Nuclear staining of constitutive androstane receptor and its downstream expression of sulfotransferases were reduced in fasting ill animals. TRH expression in the hypothalamus was not different in fasted and fed ill rabbits, although circulating TSH levels were higher with feeding. In conclusion, in this rabbit model of sustained critical illness, reduced circulating T(3), but not T(4), levels could be prevented by parenteral nutrition, which may be mediated by leptin and its actions on tissue deiodinase activity.status: publishe