Cholestasis and elevated serum bile1 acid levels are common in critically ill patients. This study aims to define the specific pattern of bile acids associated with acute respiratory distress syndrome (ARDS) and the changes in pattern over time.
Prospective observational study. Serum samples of 70 ARDS patients were analyzed for primary bile acids (cholic acid, chenodeoxycholic acid) and secondary bile acids (deoxycholic acid, litocholic acid, and ursodeoxycholic acid) as well as their glycine and taurine glycation products.
Primary bile acid levels increased from day zero to day five by almost 50% (p<0.05). This change bases on a statistically significant increase in all primary bile acids between day 0 and day 5 (cholic acid [CA] p=0.001, taurocholic acid [TCA] p=0.004, glycocholic acid [GCA] p<0.001, chenodeoxycholic acid [CDCA] p=0.036, taurochenodeoxycholic acid [TCDCA] p<0.001, glycochenodeoxycholic acid [GCDCA] p<0.001). Secondary bile acids showed predominantly decreased levels on day 0 compared to the control group and remained stable throughout the study period; the differences between day zero and day five were not statistically significant. Non-survivors exhibited significantly higher levels of TCDCA on day 5 (p<0.05) than survivors. This value was also independently associated with survival in a logistic regression model with an odds ratio of 2.24 (95% CI 0.53–9.46).
The individual bile acid profile of this ARDS patient cohort is unique compared to other disease states. The combination of changes in individual bile acids reflects a shift toward the acidic pathway of bile acid synthesis. Our results support the concept of ARDS-specific plasma levels of bile acids in a specific pattern as an adaptive response mechanism.
This research was facilitated by a generous unrestricted grant from Sartorius AG, Göttingen.
Research funding: The study was fully funded by departmental funding from the Göttingen and Jena Centers.
Author contributions: LOH initiated the trial, consented the patients, took the specimen and clinical data, condensed and analyzed the data and drafted and revised the manuscript. DM analyzed the specimen, helped with the analysis of the data, and revised the manuscript. TB and CA initiated the DACAPO trial, helped with study initiation, and revised the manuscript. MK supervised and helped to analyze the specimen, helped to analyze and interpret the data and revised the manuscript. MB helped initiating the trial and interpreting the data and revised the manuscript. OM helped analyzing and interpreting the data and revised the manuscript. MQ helped initiate the trial, analyze the data, and revised the manuscript. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: LOH received non-cash benefits from CSL Behring for advanced trainings, advisory fees from Baxter, and an unrestricted research Grant from Sartorius AG Göttingen. DM reports no conflicts of interest and did not receive any benefits. TB, CA, MK, MB: no conflicts of interest. OM received honoraria for lectures during workshops on hemodynamic monitoring, supported by Pulsion (Maquet Critical Care) and for 2 lectures during industrial sessions at national congresses (HillRom, Hepawash); unrestricted research grant from CSL Behring in 2015. MQ: Advisory Board Xenios/Fresenius, Advisory Board Baxter, Advisory Board B. Braun, member of DSMB for a study conducted by Bayer.
Informed consent: Informed consent to participate and for publication was obtained from patients where possible, otherwise next of kin/legal representatives.
Ethical approval: The study was approved by the local Research Ethics Board of Georg-August-University Goettingen (IRB No. 18/8/14 on 08.09.2014).
Data availability: Data are available upon reasonable request from the corresponding author.
Trial registration: Clinicaltrials.gov, NCT02637011. Registered 15 December 2015, https://clinicaltrials.gov/NCT02637011?cond=0;NCT02637011&draw=0;2&rank=0;1.
1. Kramer, L, Jordan, B, Druml, W, Bauer, P, Metnitz, PG. Austrian epidemiologic study on intensive care ASG. Incidence and prognosis of early hepatic dysfunction in critically ill patients–a prospective multicenter study. Crit Care Med 2007;35:1099–104, https://doi.org/10.1097/01.ccm.0000259462.97164.a0.Search in Google Scholar
2. Mesotten, D, Wauters, J, Van den Berghe, G, Wouters, PJ, Milants, I, Wilmer, A. The effect of strict blood glucose control on biliary sludge and cholestasis in critically ill patients. J Clin Endocrinol Metab 2009;94:2345–52, https://doi.org/10.1210/jc.2008-2579.Search in Google Scholar
3. Kredel, M, Brederlau, J, Roewer, N, Wunder, C. Cholestasis and liver dysfunction in critical care patients. Anaesthesist 2008;57:1172–82, https://doi.org/10.1007/s00101-008-1459-y.Search in Google Scholar
4. Krell, H, Enderle, GJ. Cholestasis: pathophysiology and pathobiochemistry. Z Gastroenterol 1993;31:11–5.Search in Google Scholar
6. Gudnason, HO, Bjornsson, ES. Secondary sclerosing cholangitis in critically ill patients: current perspectives. Clin Exp Gastroenterol 2017;10:105–11, https://doi.org/10.2147/ceg.s115518.Search in Google Scholar PubMed PubMed Central
7. Leonhardt, S, Veltzke-Schlieker, W, Adler, A, Schott, E, Hetzer, R, Schaffartzik, W, et al.. Trigger mechanisms of secondary sclerosing cholangitis in critically ill patients. Crit Care 2015;19:131, https://doi.org/10.1186/s13054-015-0861-5.Search in Google Scholar PubMed PubMed Central
11. Jenniskens, M, Langouche, L, Vanwijngaerden, YM, Mesotten, D, Van den Berghe, G. Cholestatic liver (dys)function during sepsis and other critical illnesses. Intensive Care Med 2016;42:16–27, https://doi.org/10.1007/s00134-015-4054-0.Search in Google Scholar PubMed
12. Gonnert, FA, Recknagel, P, Hilger, I, Claus, RA, Bauer, M, Kortgen, A. Hepatic excretory function in sepsis: implications from biophotonic analysis of transcellular xenobiotic transport in a rodent model. Crit Care 2013;17:R67, https://doi.org/10.1186/cc12606.Search in Google Scholar PubMed PubMed Central
13. Azer, SA, Coverdale, SA, Byth, K, Farrell, GC, Stacey, NH. Sequential changes in serum levels of individual bile acids in patients with chronic cholestatic liver disease. J Gastroenterol Hepatol 1996;11:208–15, https://doi.org/10.1111/j.1440-1746.1996.tb00064.x.Search in Google Scholar PubMed
14. Azer, SA, Stacey, NH. Current concepts of hepatic uptake, intracellular transport and biliary secretion of bile acids: physiological basis and pathophysiological changes in cholestatic liver dysfunction. J Gastroenterol Hepatol 1996;11:396–407, https://doi.org/10.1111/j.1440-1746.1996.tb01390.x.Search in Google Scholar PubMed
15. Horvatits, T, Drolz, A, Rutter, K, Roedl, K, Langouche, L, Van den Berghe, G, et al.. Circulating bile acids predict outcome in critically ill patients. Ann Intensive Care 2017;7:48, https://doi.org/10.1186/s13613-017-0272-7.Search in Google Scholar PubMed PubMed Central
17. Shin, D-J, Wang, L. Bile acid-activated receptors: a review on FXR and other nuclear receptors. In: Fiorucci, S, Distrutti, E, editors Bile acids and their receptors. Cham: Springer International Publishing; 2019:51–72 pp.10.1007/164_2019_236Search in Google Scholar PubMed
19. Fryer, RM, Ng, KJ, Nodop Mazurek, SG, Patnaude, L, Skow, DJ, Muthukumarana, A, et al.. G protein-coupled bile acid receptor 1 stimulation mediates arterial vasodilation through a K(Ca)1.1 (BK(Ca))-dependent mechanism. J Pharmacol Exp Therapeut 2014;348:421–31, https://doi.org/10.1124/jpet.113.210005.Search in Google Scholar PubMed
21. Jadeja, RN, Thounaojam, MC, Bartoli, M, Khurana, S. Deoxycholylglycine, a conjugated secondary bile acid, reduces vascular tone by attenuating Ca2+ sensitivity via rho kinase pathway. Toxicol Appl Pharmacol 2018;348:14–21, https://doi.org/10.1016/j.taap.2018.04.012.Search in Google Scholar PubMed
22. Leonhardt, J, Haider, RS, Sponholz, C, Leonhardt, S, Drube, J, Spengler, K, et al.. Circulating bile acids in liver failure activate TGR5 and induce monocyte dysfunction. Cell Mol Gastroenterol Hepatol 2021;12:25–40, https://doi.org/10.1016/j.jcmgh.2021.01.011.Search in Google Scholar PubMed PubMed Central
23. Amaral, JD, Viana, RJ, Ramalho, RM, Steer, CJ, Rodrigues, CM. Bile acids: regulation of apoptosis by ursodeoxycholic acid. J Lipid Res 2009;50:1721–34, https://doi.org/10.1194/jlr.r900011-jlr200.Search in Google Scholar PubMed PubMed Central
24. Harnisch, LO, Moerer, O. The specific bile acid profile of shock: a hypothesis generating appraisal of the literature. J Clin Med 2020;9:3844, https://doi.org/10.3390/jcm9123844.Search in Google Scholar PubMed PubMed Central
25. Maca, J, Jor, O, Holub, M, Sklienka, P, Bursa, F, Burda, M, et al.. Past and present ARDS mortality rates: a systematic review. Respir Care 2017;62:113–22, https://doi.org/10.4187/respcare.04716.Search in Google Scholar PubMed
27. De Keulenaer, BL, De Waele, JJ, Powell, B, Malbrain, ML. What is normal intra-abdominal pressure and how is it affected by positioning, body mass and positive end-expiratory pressure? Intensive Care Med 2009;35:969–76, https://doi.org/10.1007/s00134-009-1445-0.Search in Google Scholar PubMed
28. Sussman, AM, Boyd, CR, Williams, JS, DiBenedetto, RJ. Effect of positive end-expiratory pressure on intra-abdominal pressure. South Med J 1991;84:697–700, https://doi.org/10.1097/00007611-199106000-00006.Search in Google Scholar PubMed
29. Matejovic, M, Rokyta, RJr., Radermacher, P, Krouzecky, A, Sramek, V, Novak, I. Effect of prone position on hepato-splanchnic hemodynamics in acute lung injury. Intensive Care Med 2002;28:1750–5, https://doi.org/10.1007/s00134-002-1524-y.Search in Google Scholar PubMed
30. Harnisch, L-O, Baumann, S, Mihaylov, D, Kiehntopf, M, Bauer, M, Moerer, O, et al.. Biomarkers of cholestasis and liver injury in the early phase of acute respiratory distress syndrome and their pathophysiological value. Diagnostics 2021;11:2356, https://doi.org/10.3390/diagnostics11122356.Search in Google Scholar PubMed PubMed Central
31. Brandstetter, S, Dodoo-Schittko, F, Blecha, S, Sebok, P, Thomann-Hackner, K, Quintel, M, et al.. Influence of quality of care and individual patient characteristics on quality of life and return to work in survivors of the acute respiratory distress syndrome: protocol for a prospective, observational, multi-centre patient cohort study (DACAPO). BMC Health Serv Res 2015;15:563, https://doi.org/10.1186/s12913-015-1232-2.Search in Google Scholar PubMed PubMed Central
32. Statistikguru. Winsorizing Rechner, 2018. Available from: https://statistikguru.de/rechner/winsorizing-rechner.html [Accessed 31 Oct 2021].Search in Google Scholar
33. Humbert, L, Maubert, MA, Wolf, C, Duboc, H, Mahe, M, Farabos, D, et al.. Bile acid profiling in human biological samples: comparison of extraction procedures and application to normal and cholestatic patients. J Chromatogr B Analyt Technol Biomed Life Sci 2012;899:135–45, https://doi.org/10.1016/j.jchromb.2012.05.015.Search in Google Scholar
34. Sugita, T, Amano, K, Nakano, M, Masubuchi, N, Sugihara, M, Matsuura, T. Analysis of the serum bile acid composition for differential diagnosis in patients with liver disease. Gastroenterol Res Pract 2015;2015:1–10, https://doi.org/10.1155/2015/717431.Search in Google Scholar
35. Chen, J, Deng, W, Wang, J, Shao, Y, Ou, M, Ding, M. Primary bile acids as potential biomarkers for the clinical grading of intrahepatic cholestasis of pregnancy. Int J Gynaecol Obstet 2013;122:5–8, https://doi.org/10.1016/j.ijgo.2013.02.015.Search in Google Scholar
36. Horvatits, T, Drolz, A, Rutter, K, Roedl, K, Fauler, G, Muller, C, et al.. Serum bile acids in patients with hepatopulmonary syndrome. Z Gastroenterol 2017;55:361–7, https://doi.org/10.1055/s-0042-121268.Search in Google Scholar
37. Horvatits, T, Drolz, A, Roedl, K, Rutter, K, Ferlitsch, A, Fauler, G, et al.. Serum bile acids as marker for acute decompensation and acute-on-chronic liver failure in patients with non-cholestatic cirrhosis. Liver Int 2017;37:224–31, https://doi.org/10.1111/liv.13201.Search in Google Scholar
38. Russell, DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 2003;72:137–74, https://doi.org/10.1146/annurev.biochem.72.121801.161712.Search in Google Scholar
40. Fichtner, F, Moerer, O, Weber-Carstens, S, Nothacker, M, Kaisers, U, Laudi, S, et al.. Clinical guideline for treating acute respiratory insufficiency with invasive ventilation and extracorporeal membrane oxygenation: evidence-based recommendations for choosing modes and setting parameters of mechanical ventilation. Respiration 2019;98:357–72, https://doi.org/10.1159/000502157.Search in Google Scholar PubMed
41. Force, ADT, Ranieri, VM, Rubenfeld, GD, Thompson, BT, Ferguson, ND, Caldwell, E, et al.. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012;307:2526–33, https://doi.org/10.1001/jama.2012.5669.Search in Google Scholar PubMed
42. Mudaliar, S, Henry, RR, Sanyal, AJ, Morrow, L, Marschall, HU, Kipnes, M, et al.. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013;145:574–82.e1, https://doi.org/10.1053/j.gastro.2013.05.042.Search in Google Scholar PubMed
43. Chen, F, Ma, L, Dawson, PA, Sinal, CJ, Sehayek, E, Gonzalez, FJ, et al.. Liver receptor homologue-1 mediates species- and cell line-specific bile acid-dependent negative feedback regulation of the apical sodium-dependent bile acid transporter. J Biol Chem 2003;278:19909–16, https://doi.org/10.1074/jbc.m207903200.Search in Google Scholar
44. Ticho, AL, Malhotra, P, Manzella, CR, Dudeja, PK, Saksena, S, Gill, RK, et al.. S-acylation modulates the function of the apical sodium-dependent bile acid transporter in human cells. J Biol Chem 2020;295:4488–97, https://doi.org/10.1074/jbc.ra119.011032.Search in Google Scholar PubMed PubMed Central
45. Vanwijngaerden, YM, Wauters, J, Langouche, L, Vander Perre, S, Liddle, C, Coulter, S, et al.. Critical illness evokes elevated circulating bile acids related to altered hepatic transporter and nuclear receptor expression. Hepatology 2011;54:1741–52, https://doi.org/10.1002/hep.24582.Search in Google Scholar PubMed
46. Lia, A, Hallmans, G, Sandberg, AS, Sundberg, B, Aman, P, Andersson, H. Oat beta-glucan increases bile acid excretion and a fiber-rich barley fraction increases cholesterol excretion in ileostomy subjects. Am J Clin Nutr 1995;62:1245–51, https://doi.org/10.1093/ajcn/62.6.1245.Search in Google Scholar PubMed
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