Z Gastroenterol 2017; 55(04): 361-367
DOI: 10.1055/s-0042-121268
Originalarbeit
© Georg Thieme Verlag KG Stuttgart · New York

Serum bile acids in patients with hepatopulmonary syndrome

Gallensäuren im Serum bei hepatopulmonalem Syndrom
Thomas Horvatits
1   Dep. Internal Medicine 3, Div. Gastroenterology & Hepatology, Medical University of Vienna, Austria
2   Dep. of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Germany
,
Andreas Drolz
1   Dep. Internal Medicine 3, Div. Gastroenterology & Hepatology, Medical University of Vienna, Austria
2   Dep. of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Germany
,
Karoline Rutter
1   Dep. Internal Medicine 3, Div. Gastroenterology & Hepatology, Medical University of Vienna, Austria
2   Dep. of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Germany
,
Kevin Roedl
1   Dep. Internal Medicine 3, Div. Gastroenterology & Hepatology, Medical University of Vienna, Austria
2   Dep. of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Germany
,
Günter Fauler
3   Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria
,
Christian Müller
1   Dep. Internal Medicine 3, Div. Gastroenterology & Hepatology, Medical University of Vienna, Austria
,
Stefan Kluge
2   Dep. of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Germany
,
Michael Trauner
1   Dep. Internal Medicine 3, Div. Gastroenterology & Hepatology, Medical University of Vienna, Austria
,
Peter Schenk
1   Dep. Internal Medicine 3, Div. Gastroenterology & Hepatology, Medical University of Vienna, Austria
,
Valentin Fuhrmann
1   Dep. Internal Medicine 3, Div. Gastroenterology & Hepatology, Medical University of Vienna, Austria
2   Dep. of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Germany
› Author Affiliations
Further Information

Publication History

29 August 2016

04 November 2016

Publication Date:
12 December 2016 (online)

Zusammenfassung

Fragestellung Das hepatopulmonale Syndrom (HPS) ist eine Störung der arteriellen Oxygenierung, welche bei bis zu 30 % der Patienten mit Leberzirrhose auftritt und mit deutlich erhöhter Sterblichkeit einhergeht. Ikterus und cholestatische Dysfunktion sind von zentraler pathogenetischer Rolle in akuter als auch chronischer Lebererkrankung.

Ziel Deshalb war es Ziel dieser Studie den Stellenwert der Serum-Gallensäuren bei Patienten mit HPS zu untersuchen.

Methodik 74 Patienten mit Leberzirrhose wurden in diese Studie eingeschlossen. Cholestasemarker, Gesamt- als auch individuelle Gallensäuren wurden bestimmt und alle Patienten auf das Vorhandensein von HPS gescreent. 26 Patienten (35 %) erfüllten die Kriterien für HPS.

Ergebnisse Serum-Gallensäuren waren signifikant höher bei Patienten mit HPS im Vergleich zu denen ohne (mediane Gesamt-Gallensäuren 83,5 μmol/l, IQR 43,1 – 148,9 vs. 26,9 μmol/l, 11 – 75,6; p < 0,001) und korrelierten mit dem Schweregrad der Blutgasaustauschstörung anhand von PaO2 and AaPO2 (p < 0,01). Serum-Gesamt-Gallensäuren zeigten sich prädiktiv für das Vorhandensein von HPS - unabhängig von Alter oder Schweregrad der Lebererkrankung (OR: 1,012, 95 % CI: 1,001 – 1,023, p < 0,05).

Schlussfolgerung Serum-Gallensäuren sind mit dem Vorhandensein von HPS assoziiert und korrelieren mit dem Schweregrad der Butgasaustauschstörung. Zukünftige Studien sollten den Stellenwert der Gallensäuren bei HPS sowie den Einfluss einer direkten Regulation des Gallensäure-Metabolismus untersuchen.

Abstract

Background Hepatopulmonary syndrome (HPS) occurs in 20 – 30 % of patients with cirrhosis and is associated with increased mortality. Cholestasis and accumulation of bile acids (BAs) play a major role in chronic liver disease.

Aim We aimed to evaluate the clinical role of serum BAs in patients with HPS.

Methods Seventy-four patients with cirrhosis were included in this prospective study. Marker for cholestasis as total and individual serum BAs, bilirubin, alkaline phosphatase (AP), and gamma-glutamyl transpeptidase (GGT) were analyzed in patients screened for HPS. Criteria of HPS were fulfilled in 26 patients (35 %).

Results In contrast to AP and GGT, bilirubin and serum BAs were significantly elevated in patients with HPS (median total BAs in HPS 83.5 μmol/L, IQR 43.1 – 148.9 vs. no HPS 26.9 μmol/L, 11 – 75.6; p < 0.001). Total BAs correlated with gas exchange by means of PaO2 / AaPO2 (r: −0.28, p < 0.05; r: 0.24, p < 0.05) and portal pressure (r: 0.33, p < 0.05). BAs were associated with HPS independently severity of underlying liver disease (OR: 1.012, 95 % CI: 1.001 – 1.023, p < 0.05).

Conclusion BA retention is associated with HPS and gas exchange abnormalities. Future studies should assess whether modulation of BAs signaling may impact the course of HPS.

 
  • References

  • 1 Rodriguez-Roisin R. Krowka MJ. Herve P. et al. Pulmonary-Hepatic vascular Disorders (PHD). Eur Respir J 2004; 24: 861-880
  • 2 Machicao VI. Balakrishnan M. Fallon MB. Pulmonary complications in chronic liver disease. Hepatology 2014; 59: 1627-1637
  • 3 Horvatits T. Fuhrmann V. Therapeutic options in pulmonary hepatic vascular diseases. Expert Rev Clin Pharmacol 2013; 7: 31-42
  • 4 Horvatits T. Drolz A. Roedl K. et al. Von Willebrand factor antigen for detection of hepatopulmonary syndrome in patients with cirrhosis. J Hepatol 2014; 61: 544-549
  • 5 Rodriguez-Roisin R. Krowka MJ. Hepatopulmonary syndrome--a liver-induced lung vascular disorder. N Engl J Med 2008; 358: 2378-2387
  • 6 Horvatits T. Fuhrmann V. Therapeutic options in pulmonary hepatic vascular diseases. Expert Rev Clin Pharmacol 2014; 7: 31-42
  • 7 Fritz JS. Fallon MB. Kawut SM. Pulmonary vascular complications of liver disease. Am J Respir Crit Care Med 2013; 187: 133-143
  • 8 Trauner M. Fickert P. Halilbasic E. et al. Lessons from the toxic bile concept for the pathogenesis and treatment of cholestatic liver diseases. Wien Med Wochenschr 2008; 158: 542-548
  • 9 Horvatits T. Trauner M. Fuhrmann V. Hypoxic liver injury and cholestasis in critically ill patients. Curr Opin Crit Care 2013; 19: 128-132
  • 10 Perez MJ. Briz O. Bile-acid-induced cell injury and protection. World J Gastroenterol 2009; 15: 1677-1689
  • 11 Li T. Chiang JY. Bile acids as metabolic regulators. Curr Opin Gastroenterol 2015; 31: 159-165
  • 12 Mannes GA. Thieme C. Stellaard F. et al. Prognostic significance of serum bile acids in cirrhosis. Hepatology 1986; 6: 50-53
  • 13 Horvatits T. Drolz A. Roedl K. et al. Serum bile acids as marker for acute decompensation and acute-on-chronic liver failure in patients with non-cholestatic cirrhosis. Liver Int 2016; [Epub ahead of print]
  • 14 Portincasa P. Grattagliano I. Testini M. et al. Parallel intestinal and liver injury during early cholestasis in the rat: modulation by bile salts and antioxidants. Free Radic Biol Med 2007; 42: 1381-1391
  • 15 Thomas C. Pellicciari R. Pruzanski M. et al. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov 2008; 7: 678-693
  • 16 Attili AF. Angelico M. Cantafora A. et al. Bile acid-induced liver toxicity: relation to the hydrophobic-hydrophilic balance of bile acids. Med Hypotheses 1986; 19: 57-69
  • 17 Javitt NB. Cholesterol, hydroxycholesterols, and bile acids. Biochem Biophys Res Commun 2002; 292: 1147-1153
  • 18 Recknagel P. Gonnert FA. Westermann M. et al. Liver dysfunction and phosphatidylinositol-3-kinase signalling in early sepsis: experimental studies in rodent models of peritonitis. PLoS Med 2012; 9: e1001338
  • 19 Yerushalmi B. Dahl R. Devereaux MW. et al. Bile acid-induced rat hepatocyte apoptosis is inhibited by antioxidants and blockers of the mitochondrial permeability transition. Hepatology 2001; 33: 616-626
  • 20 Halilbasic E. Claudel T. Trauner M. Bile acid transporters and regulatory nuclear receptors in the liver and beyond. J Hepatol 2013; 58: 155-168
  • 21 Wang L. Zhuang L. Rong H. et al. MicroRNA-101 inhibits proliferation of pulmonary microvascular endothelial cells in a rat model of hepatopulmonary syndrome by targeting the JAK2 / STAT3 signaling pathway. Mol Med Rep 2015; 12: 8261-8267
  • 22 Trauner M. Fickert P. Stauber RE. Inflammation-induced cholestasis. J Gastroenterol Hepatol 1999; 14: 946-959
  • 23 Moseley RH. Sepsis-associated cholestasis. Gastroenterology 1997; 112: 302-306
  • 24 Geier A. Fickert P. Trauner M. Mechanisms of disease: mechanisms and clinical implications of cholestasis in sepsis. Nat Clin Pract Gastroenterol Hepatol 2006; 3: 574-585
  • 25 Allen K. Jaeschke H. Copple BL. Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. Am J Pathol 2011; 178: 175-186
  • 26 Fryer RM. Ng KJ. Nodop Mazurek SG. 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 Ther 2014; 348: 421-431
  • 27 Khurana S. Raufman JP. Pallone TL. Bile acids regulate cardiovascular function. Clin Transl Sci 2011; 4: 210-218
  • 28 Peck-Radosavljevic M. Angermayr B. Datz C. et al. Austrian consensus on the definition and treatment of portal hypertension and its complications (Billroth II). Wien Klin Wochenschr 2013; 125: 200-219
  • 29 de Franchis R. Baveno VIF. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015; 63: 743-752
  • 30 Jager B. Drolz A. Michl B. et al. Jaundice increases the rate of complications and one-year mortality in patients with hypoxic hepatitis. Hepatology 2012; 56: 2297-2304
  • 31 Jonsson G. Hedenborg G. Wisen O. et al. Serum concentrations and excretion of bile acids in cirrhosis. Scand J Clin Lab Invest 1992; 52: 599-605
  • 32 Neale G. Lewis B. Weaver V. et al. Serum bile acids in liver disease. Gut 1971; 12: 145-152
  • 33 Luo B. Abrams GA. Fallon MB. Endothelin-1 in the rat bile duct ligation model of hepatopulmonary syndrome: correlation with pulmonary dysfunction. J Hepatol 1998; 29: 571-578
  • 34 Luo B. Liu L. Tang L. et al. Increased pulmonary vascular endothelin B receptor expression and responsiveness to endothelin-1 in cirrhotic and portal hypertensive rats: a potential mechanism in experimental hepatopulmonary syndrome. J Hepatol 2003; 38: 556-563
  • 35 Horvatits T. Drolz A. Rutter K. et al. Pulmonary complications in liver diseases. Med Klin Intensivmed Notfmed 2014; 109: 235-239
  • 36 Raevens S. Coulon S. Van Steenkiste C. et al. Role of angiogenic factors/cell adhesion markers in serum of cirrhotic patients with hepatopulmonary syndrome. Liver Int 2015; 35: 1499-1507
  • 37 Zhang J. Fallon MB. Hepatopulmonary syndrome: update on pathogenesis and clinical features. Nat Rev Gastroenterol Hepatol 2012; 9: 539-549
  • 38 Zhang J. Yang W. Luo B. et al. The role of CX(3)CL1/CX(3)CR1 in pulmonary angiogenesis and intravascular monocyte accumulation in rat experimental hepatopulmonary syndrome. J Hepatol 2012; 57: 752-758
  • 39 Chang CC. Wang SS. Hsieh HG. et al. Rosuvastatin improves hepatopulmonary syndrome through inhibition of inflammatory angiogenesis of lung. Clin Sci (Lond) 2015; 129: 449-460
  • 40 Zeng J. Chen L. Chen B. et al. MicroRNA-199a-5p Regulates the Proliferation of Pulmonary Microvascular Endothelial Cells in Hepatopulmonary Syndrome. Cell Physiol Biochem 2015; 37: 1289-1300
  • 41 Fallon MB. Abrams GA. McGrath JW. et al. Common bile duct ligation in the rat: a model of intrapulmonary vasodilatation and hepatopulmonary syndrome. Am J Physiol 1997; 272: G779-G784
  • 42 Yang Y. Chen B. Chen Y. et al. A comparison of two common bile duct ligation methods to establish hepatopulmonary syndrome animal models. Lab Anim 2015; 49: 71-79
  • 43 Tag CG. Sauer-Lehnen S. Weiskirchen S. et al. Bile duct ligation in mice: induction of inflammatory liver injury and fibrosis by obstructive cholestasis. J Vis Exp 2015;
  • 44 Kinugasa T. Uchida K. Kadowaki M. et al. Effect of bile duct ligation on bile acid metabolism in rats. J Lipid Res 1981; 22: 201-207
  • 45 Zhang Y. Hong JY. Rockwell CE. et al. Effect of bile duct ligation on bile acid composition in mouse serum and liver. Liver Int 2012; 32: 58-69
  • 46 Jalan R. Fernandez J. Wiest R. et al. Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013. J Hepatol 2014; 60: 1310-1324
  • 47 Sztrymf B. Rabiller A. Nunes H. et al. Prevention of hepatopulmonary syndrome and hyperdynamic state by pentoxifylline in cirrhotic rats. Eur Respir J 2004; 23: 752-758
  • 48 Rabiller A. Nunes H. Lebrec D. et al. Prevention of gram-negative translocation reduces the severity of hepatopulmonary syndrome. Am J Respir Crit Care Med 2002; 166: 514-517
  • 49 Fallon MB. Abrams GA. Luo B. et al. The role of endothelial nitric oxide synthase in the pathogenesis of a rat model of hepatopulmonary syndrome. Gastroenterology 1997; 113: 606-614
  • 50 Lan T. Haywood J. Dawson PA. Inhibition of ileal apical but not basolateral bile acid transport reduces atherosclerosis in apoE(-)/(-) mice. Atherosclerosis 2013; 229: 374-380
  • 51 Singh N. Yadav M. Singh AK. et al. Synthetic FXR agonist GW4064 is a modulator of multiple G protein-coupled receptors. Mol Endocrinol 2014; 28: 659-673