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106 ADRENAL DYSFUNCTION IN NONSEPTIC CIRRHOTIC PATIENTS WITH ASCITES: IMPACT ON SURVIVAL
ORAL PRESENTATIONS Parallel Session: PORTAL HYPERTENSION
106 ADRENAL DYSFUNCTION IN NONSEPTIC CIRRHOTIC PATIENTS WITH ASCITES: IMPACT ON SURVIVAL C. Elia, C. Alessandria, L. Mezzabotta, A. Risso, A. Andrealli, M. Spandre, A. Morgando, A. Marzano, M. Rizzetto. Gastroenterology and Hepatology, San Giovanni Battista Hospital, Torino, Italy E-mail: [email protected] Background: Adrenal dysfunction (AD) is an emerging issue in end-stage liver disease. In cirrhotics with severe sepsis and septic shock it was associated with poor prognosis. Its clinical relevance and impact on survival in nonseptic cirrhotic patients are almost unknown. Aims: To evaluate the impact of AD on survival in nonseptic cirrhotic patients with ascites. Patients and Methods: A corticotropin stimulation test (tetracosactide 250 mg i.v) was performed in a series of consecutive cirrhotic patients with ascites; all were haemodynamically stable and without clinical or laboratory signs of sepsis. AD was defined by a “delta cortisol” lower than 9 mg /dL and/or a “peak cortisol” lower than 18 mg /dL. Patients were followed-up until liver transplantation or death. Results: Eighty-five patients were included. Overall AD prevalence was 39% (33/85). Median follow-up was 198 days (range 3–1031). Sixteen patients died, 11 (group 1) among patients with AD (11/33, 33%; median survival: 170 days, range 9–1031) and 5 (group 2) among patients without AD (5/52, 10%; median survival: 212 days, range 3–949). The most common cause of death was liver failure (5/11 pts in group 1 vs 2/5 pts in group 2), followed by hepatorenal syndrome type 1 (1/11 pts in group 1 vs 3/5 pts in group 2), sepsis (3 pts, all in group 1) and portal hypertension related bleeding (2 pts, all in group 1). The proportions of the causes of death were not significantly different between the two groups (p = ns). At univariate analysis, MELD score (p = 0.003), AD (p = 0.02), Child– Pugh score (p = 0.04) and plasma renin activity (p = 0.04) were significantly associated with mortality. Even at multivariate analysis AD was significantly associated with reduced survival (p = 0.03), together with MELD score (p = 0.02) and plasma renin activity (p = 0.03). Conclusions: Adrenal dysfunction is common in nonseptic cirrhotic patients and, according to our preliminary results, its presence is independently associated with reduced survival. These findings highlight the clinical relevance of adrenal dysfunction in nonseptic cirrhotic patients with ascites. 107 EFFECTS OF SIMVASTATIN ADMINISTRATION ON LIVER MICROVASCULAR DYSFUNCTION INDUCED BY LPS V. La Mura, M. Pasar´ın, J.C. Garc´ıa-Pagan, ´ J.G. Abraldes, J. Bosch. Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Cl´ınic-IDIBAPS and Centro de Investigaci´ on Biom´edica en Red de Enfermedades Hep´ aticas y Digestivas, Barcelona, Spain E-mail: [email protected] Background and Aims: Endothelial dysfunction at the microvasculature contributes to organ failure in sepsis. We have recently shown that LPS injection is followed after 24 hours by the development of liver sinusoidal endothelial dysfunction in a rat model of endotoxemia, which could contribute to liver dysfunction during sepsis. Recent experimental data in experimental models and observational data in humans suggest that statins might improve vascular inflammation and microvascular dysfunction in S48
sepsis. However, the potential of these drugs for preventing sepsisinduced liver vascular abnormalities have never been explored. This study aimed at evaluating whether the administration of simvastatin could have protective vascular effects at the liver in a rat model of endotoxemia. Methods: All experiments were conducted in male wistar rats. The effects of LPS (5 mg/kg i.p.) as compared with saline injection were tested in 3 groups of rats; A: rats treated with placebo; B: rats treated with simvastatin (25 mg/kg, p.o.), given 3 and 23 h. after LPS/saline challenge; C: rats treated with simvastatin (25 mg/kg/24 h, p.o.) from 3 days before LPS/saline injection, with the last dose 1 hour before the hemodynamic study. After 24 hours of LPS/saline injection livers were isolated, perfused and preconstricted with methoxamine (10−4 M). Sinusoidal endothelial function was explored by testing the vasodilation of the liver circulation to increasing concentrations of acetylcholine (10−7 , 10−6 , 10−5 M). Results: In rats treated with placebo LPS administration induced an increase in baseline portal perfusion pressure, a decrease in the response to methoxamine and a marked decrease in the vasodilation to acetylcholine (demonstrating sinusoidal endothelial dysfunction). Simvastatin administration after LPS challenge did not prevent the increase in baseline portal perfusion pressure or the hyporesponse to methoxamine, but attenuated the development of sinusoidal endothelial dysfunction. Treatment with simvastatin from 3 days before LPS administration prevented the increase in baseline perfusion pressure and totally normalized the vasodilating response of the liver vasculature to acetylcholine. Conclusion: The administration with simvastatin, especially when given before LPS challenge, protects from the development of liver microvascular dysfunction in a rat model of sepsis. This suggests that simvastatin might have potential for the prevention of liver dysfunction during sepsis.
Figure: response to ACh.
108 ASSOCIATION OF GENES REGULATING VITAMIN D HOMEOSTASIS WITH VITAMIN D LEVELS AND LIVER FIBROSIS IN A COHORT OF PATIENTS WITH CHRONIC LIVER DISEASE 1 F. Grunhage ¨ , K. Hochrath1 , M. Krawczyk1 , B. Obermayer-Pietsch2 , M. Trauner3 , F. Lammert1 . 1 Department of Medicine II, Saarland University Hospital, Homburg, Germany; 2 Department of Internal Medicine, Medical University of Graz, Graz, 3 Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria E-mail: [email protected] Background: Recently, genome wide studies identified a number of genetic variants that affect on vitamin D levels in healthy populations (rs12785878, near DHCR7; rs10741657, near CYP2R1 and rs7041 vitamin D binding protein GC; Wang et al. Lancet 2010). Since vitamin D deficiency is associated with advanced liver disease, we hypothesized that these variants are associated with vitamin D levels and fibrosis in patients with chronic liver disease. Patients and Methods: Overall, 834 patients with chronic liver disease and predominantly Caucasian descent (n = 712; 85%) were included. Levels of 25(OH)-vitamin D3 were determined and liver stiffness was measured using transient elastography (TE). Patients were stratified in different fibrosis stages according to TE results
Journal of Hepatology 2011 vol. 54 | S45–S60
106 ADRENAL DYSFUNCTION IN NONSEPTIC CIRRHOTIC PATIENTS WITH ASCITES: IMPACT ON SURVIVAL C. Elia, C. Alessandria, L. Mezzabotta, A. Risso, A. Andrealli, M. Spandre, A. Morgando, A. Marzano, M. Rizzetto. Gastroenterology and Hepatology, San Giovanni Battista Hospital, Torino, Italy E-mail: [email protected] Background: Adrenal dysfunction (AD) is an emerging issue in end-stage liver disease. In cirrhotics with severe sepsis and septic shock it was associated with poor prognosis. Its clinical relevance and impact on survival in nonseptic cirrhotic patients are almost unknown. Aims: To evaluate the impact of AD on survival in nonseptic cirrhotic patients with ascites. Patients and Methods: A corticotropin stimulation test (tetracosactide 250 mg i.v) was performed in a series of consecutive cirrhotic patients with ascites; all were haemodynamically stable and without clinical or laboratory signs of sepsis. AD was defined by a “delta cortisol” lower than 9 mg /dL and/or a “peak cortisol” lower than 18 mg /dL. Patients were followed-up until liver transplantation or death. Results: Eighty-five patients were included. Overall AD prevalence was 39% (33/85). Median follow-up was 198 days (range 3–1031). Sixteen patients died, 11 (group 1) among patients with AD (11/33, 33%; median survival: 170 days, range 9–1031) and 5 (group 2) among patients without AD (5/52, 10%; median survival: 212 days, range 3–949). The most common cause of death was liver failure (5/11 pts in group 1 vs 2/5 pts in group 2), followed by hepatorenal syndrome type 1 (1/11 pts in group 1 vs 3/5 pts in group 2), sepsis (3 pts, all in group 1) and portal hypertension related bleeding (2 pts, all in group 1). The proportions of the causes of death were not significantly different between the two groups (p = ns). At univariate analysis, MELD score (p = 0.003), AD (p = 0.02), Child– Pugh score (p = 0.04) and plasma renin activity (p = 0.04) were significantly associated with mortality. Even at multivariate analysis AD was significantly associated with reduced survival (p = 0.03), together with MELD score (p = 0.02) and plasma renin activity (p = 0.03). Conclusions: Adrenal dysfunction is common in nonseptic cirrhotic patients and, according to our preliminary results, its presence is independently associated with reduced survival. These findings highlight the clinical relevance of adrenal dysfunction in nonseptic cirrhotic patients with ascites. 107 EFFECTS OF SIMVASTATIN ADMINISTRATION ON LIVER MICROVASCULAR DYSFUNCTION INDUCED BY LPS V. La Mura, M. Pasar´ın, J.C. Garc´ıa-Pagan, ´ J.G. Abraldes, J. Bosch. Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Cl´ınic-IDIBAPS and Centro de Investigaci´ on Biom´edica en Red de Enfermedades Hep´ aticas y Digestivas, Barcelona, Spain E-mail: [email protected] Background and Aims: Endothelial dysfunction at the microvasculature contributes to organ failure in sepsis. We have recently shown that LPS injection is followed after 24 hours by the development of liver sinusoidal endothelial dysfunction in a rat model of endotoxemia, which could contribute to liver dysfunction during sepsis. Recent experimental data in experimental models and observational data in humans suggest that statins might improve vascular inflammation and microvascular dysfunction in S48
sepsis. However, the potential of these drugs for preventing sepsisinduced liver vascular abnormalities have never been explored. This study aimed at evaluating whether the administration of simvastatin could have protective vascular effects at the liver in a rat model of endotoxemia. Methods: All experiments were conducted in male wistar rats. The effects of LPS (5 mg/kg i.p.) as compared with saline injection were tested in 3 groups of rats; A: rats treated with placebo; B: rats treated with simvastatin (25 mg/kg, p.o.), given 3 and 23 h. after LPS/saline challenge; C: rats treated with simvastatin (25 mg/kg/24 h, p.o.) from 3 days before LPS/saline injection, with the last dose 1 hour before the hemodynamic study. After 24 hours of LPS/saline injection livers were isolated, perfused and preconstricted with methoxamine (10−4 M). Sinusoidal endothelial function was explored by testing the vasodilation of the liver circulation to increasing concentrations of acetylcholine (10−7 , 10−6 , 10−5 M). Results: In rats treated with placebo LPS administration induced an increase in baseline portal perfusion pressure, a decrease in the response to methoxamine and a marked decrease in the vasodilation to acetylcholine (demonstrating sinusoidal endothelial dysfunction). Simvastatin administration after LPS challenge did not prevent the increase in baseline portal perfusion pressure or the hyporesponse to methoxamine, but attenuated the development of sinusoidal endothelial dysfunction. Treatment with simvastatin from 3 days before LPS administration prevented the increase in baseline perfusion pressure and totally normalized the vasodilating response of the liver vasculature to acetylcholine. Conclusion: The administration with simvastatin, especially when given before LPS challenge, protects from the development of liver microvascular dysfunction in a rat model of sepsis. This suggests that simvastatin might have potential for the prevention of liver dysfunction during sepsis.
Figure: response to ACh.
108 ASSOCIATION OF GENES REGULATING VITAMIN D HOMEOSTASIS WITH VITAMIN D LEVELS AND LIVER FIBROSIS IN A COHORT OF PATIENTS WITH CHRONIC LIVER DISEASE 1 F. Grunhage ¨ , K. Hochrath1 , M. Krawczyk1 , B. Obermayer-Pietsch2 , M. Trauner3 , F. Lammert1 . 1 Department of Medicine II, Saarland University Hospital, Homburg, Germany; 2 Department of Internal Medicine, Medical University of Graz, Graz, 3 Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria E-mail: [email protected] Background: Recently, genome wide studies identified a number of genetic variants that affect on vitamin D levels in healthy populations (rs12785878, near DHCR7; rs10741657, near CYP2R1 and rs7041 vitamin D binding protein GC; Wang et al. Lancet 2010). Since vitamin D deficiency is associated with advanced liver disease, we hypothesized that these variants are associated with vitamin D levels and fibrosis in patients with chronic liver disease. Patients and Methods: Overall, 834 patients with chronic liver disease and predominantly Caucasian descent (n = 712; 85%) were included. Levels of 25(OH)-vitamin D3 were determined and liver stiffness was measured using transient elastography (TE). Patients were stratified in different fibrosis stages according to TE results
Journal of Hepatology 2011 vol. 54 | S45–S60