Bacterial translocation in cirrhosis

Transcription

1 Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation Dept. of Medicine University of Padova, Italy AISF Monothematic Conference 2012 The Gut-Liver axis: a bidiretional relation in health and disease Bologna October 4-5th

2 Definition Bacterial translocation (BT), is defined as the migration of viable bacteria or bacterial products from the intestinal lumen to mesenteric lymph nodes (MLNs) or other extraintestinal organs and sites. R. Wiest et al. Hepatology 2005 ; 41 :

3 Bacterial DNA fragments in mesenteric lymph nodes (MLNs) in cirrhotic rats according to positive cultures from MLNs 100 % Controls Cirrhotic rats with GBT Cirrhotic rats without GBT Non ascites Ascites M. Ubeda et al. Hepatology 2010 ; 52 :

4 Headlines Prevalence Pathogenesis Pathophysiological consequences Clinical consequences Prevention

5 Positive cultures from mesenteric lymph nodes in cirrhotic patients (pts) according to the Child-Turcotte-Pugh (CTP) class and selective intestinal decontamination (SID) 100 (%) 75 P < Controls Cirrhotic pts CTP A Cirrhotic pts CTP B Cirrhotic pts CTP C Cirrhotic pts with SID I. Cicera et al. J. Hepatol ; 34 : 32-37

6 Markers of bacterial translocation Bact-DNA Bacterial footprints Endotoxins (LPS) LPS binding protein

7 Plasma levels of lipopolysaccharide (LPS) binding protein (LBP) in patients with cirrhosis and ascites LBP (µg/ml) % Cirrhotics with ascites Cirrhotic without ascites Normal subjects A. Albillos et al. Hepatology 2003 ; 37:

8 Bacterial tranlocation (BT) Prevalence of Bact-DNA in inpatients with cirrhosis and refcractory ascites 36.6% Bact-DNA-ve patients Bact-DNA+ve patients 63.4% S. aureus 26.9% E. fecium 7.7% E. coli 57.7% 7.7% K. pneumoniae P. Angeli et al. (AASLD Annual Meeting 2010)

9 Headlines Prevalence Pathogenesis Pathophysiological consequences Clinical consequences Prevention

10 Mechanisms of bacterial translocation R. Wiest et al. Hepatology 2005 ; 41 :

11 Small intestine bacterial overgrowth in cirrhotic patients according with the occurrence of SBP 100 (%) 75 P < SBP No SBP CS. Chang et al. Hepatology 1998 ; 28 :

12 The Bifidobacteria/Enterobacteriaceae ratio in patients with decompensated cirrhosis 2,0 1,5 P <0.01 1,0 0,5 0,0 Healthy controls Patients with cirrhosis H. Lu et al. Micriobiol. Ecol ; 61 :

13 Phylogenetic groups of E. coli. in patients with cirrhosis and spontaneous bacterial peritotinitis and/or bacteremia 60 % Group A Group B1 Group B2 Group D F. Bert et al. J. Clin. Microbiol : 48 :

14 F. Bert et al. J. Clin. Microbiol : 48 :

15 Factors contributing to the bacterial overgrowth in cirrhotic patients Reduced gastric acid secretion Reduced intestinal peristalsis Reduced bile ouput and/or abnormal bile composition Reduced intestinal mucosa secretion and/or abnormal composition Deficit of the mucosal immunity

16 Drugs used only for a liver-related condition in hospitalized patients with cirrhosis in Spain % Diuretics Antiulcer drugs Laxatives Vitamin K Betablockers Nitrates On admission At discharge MI. Lucena et al. Eur. J. Clin. Pharmacol ; 58 :

17 Use of proton pump inhibitors (PPI) in patients with cirrhosis and spontaneous bacterial peritonitis 100 (%) 80 P < Appropriate PPI use SBP Appropriate PPI use No SBP JS. Bajaj,et al. Am. J. Gastroenterol ; 104 :

18 Expression of Paneth cell antimicrobial peptides in control patients (C), patients with liver cirrhosis (LC) and patients with LC and bacterial translocation (LC + BT) C LC LC+BT C LC LC+BT C LC LC+BT R. Wiest et al. Hepatology 2005 ; 41 :

19 Mechanisms of bacterial translocation R. Wiest et al. Hepatology 2005 ; 41 :

20 Percentage of urine excretion of a marker of integrity of mucosal barrier in cirrhotic patients 40 (%) 30 P < Control subjectcs Patients with cirrhosis C. Ersoz et al. Eur. J. Gastroenterol. Hepatol ; 11 :

21 Mechanisms of bacterial translocation R. Wiest et al. Hepatology 2005 ; 41 :

22 MLCK regulates ZO-1 exchange in vivo. Schematic diagram of the molecular organization of epithelial tight junction Yu D et al. PNAS 2010;107: by National Academy of Sciences Université de Genève 2011

23 MLCK regulates ZO-1 exchange in vivo. Bacterial translocation (BT) Occludin expression 1 day after ligation of the common bile duct (BDL) 2,5 2,0 1,5 P <0.05 1,0 0,5 0,0 Baseline 1 Day Yu D et al. PNAS 2010;107: DE. Fouts et al. J. Hepatol ; 56 : by National Academy of Sciences

24 MLCK regulates ZO-1 exchange in vivo. Schematic diagram of the molecular organization of epithelial tight junction Yu D et al. PNAS 2010;107: by National Academy of Sciences Université de Genève 2011

25 Mechanisms of bacterial translocation R. Wiest et al. Hepatology 2005 ; 41 :

26 Model for a role of Nod1 and Nod2 as cytosolic surveillance proteins of mucosal surfaces M. Chamaillard et al. Cell. Microbiol :

27 Nucleotide-binding oligomerization domain containing 2 (NOD2) Variants as a risk factors for spontaneous bacterial peritonitis in patients with cirrhosis B. Appenrodt et al. Hepatology 2010 ; 51 :

28 Acute (ALF), chronic (CLF) or acute on chronic liver failure (ACLF) The expressions of TNFα- and IL-10 positive cells within the liver tissue Zou ZH. et al. J. Clin. Gastroenterol ; 43 :

29 Model for a role of Nod1 and Nod2 as cytosolic surveillance proteins of mucosal surfaces MLCK M. Chamaillard et al. Cell. Microbiol :

30 Myosin II regulatory light chainkinase (MLCK) phosphorylation 3,0 2,5 P < ,0 1,5 1,0 0,5 0,0 γ γ γ α Control IFN TNF IFN + TNF F. Wang et al. Am. J. Pathol ; 166 :

31 Cultured intestinal epithelial cell permeability to 3kD fluorescein isothiocyanate-dextran exposed to IFN-γ followed by TNF-α 30 KD Dextran flux P < Control IFN γ TNF α IFN γ + TNF α F. Wang et al. Am. J. Pathol ; 166 :

32 Headlines Prevalence Pathogenesis Pathophysiological consequences Clinical consequences Prevention

33 Endotoxins and proinflammatory citokines Increasing rate of BT

34 Bacterial translocation in cirrhosis: clinical consequences Bacterial infections Cardiovascular dysfunction Renal failure Hepatic encephalophaty

35 Bacterial translocation in cirrhosis: consequences Viable Bacteria Translocation Bacterial infection LPS TNFα SIRS

36 Actuarial probability of severe bacterial infetions in patients with cirrhosis and ascites according to the plasma level of lipopolysaccharide-binding protein (LBP) A. Albillos et al. Lancet 2004 ; 363 :

37 Bacterial translocation in cirrhosis: consequences Bacterial fragments Translocation Bacterial infection LPS LPS TNFα SIRS

38 Tumor necrosis factor α (TNFα) and Interferon γ (INFγ levels in cirrhotic patients with ascites N.S. N.S. (pg/ml) Serum TNFα Serum IFNγ Bact-DNA-ve Bact-DNA+ve SBP R. Frances et al. Hepatology 2008 ; 47 :

39 Molecular translocation persists during i.v. antibiotic tretament of SBP episodes R. Frances et al. Hepatology 2008 ; 47 :

40 Bacterial translocation in cirrhosis: clinical consequences Bacterial infections Cardiovascular dysfunction Renal failure Hepatic encephalophaty

41 Six month follow up of patients with cirrhosis and refractory ascites according to the detection of Bact-DNA in ascites Event Bact-DNA+ve Bact-DNA-ve p value (n= 23) (n= 14) All complications 96% 64% < 0.05 HRS 1 26% 0 % < 0.05 Death 46% 14% < 0.05 P. Angeli et al. (AASLD Annual Meeting 2010)

42 Endotoxins and proinflammatory citokines Further derangement of Systemic heamodynamics Fibrosis progression in the liver dnd increase in portal pressure Organ failure(s)

43 TLR4 expression in the Bile duct ligated and in the BDL + LPS group N. Shah et al. Journal of Hepatology 2012 vol. 56 j

44 Methamine silver staining of the kidney in the BDL group and in the BDL group administered LPS (BDL+LPS group) N. Shah et al. Journal of Hepatology 2012 vol. 56 j

45 Bacterial translocation in cirrhosis: clinical consequences Bacterial infections Cardiovascular dysfunction Renal failure Hepatic encephalophaty

46 Bacterial translocation (BT) Activation state of CD103+ dendritic cells in mesenteric lymph nodes of control rats and cirrhotic rats according to the Bact-DNA state and gut viable bacteria translocation (GBT) 0 Control rats Cirrhotic rats BactDNA-ve and GBT-ve Cirrhotic rats BactDNA+ve and GBT-ve Cirrhotic rats GBT+ve L. Munoz et al. Hepatology 2012 (Epub ahead of print)

47 Bcterial translocation (BT) Schematic representation of the in vitro model of functional monocyte decativation GA. Antoniades et al. J. Hepatol ; 49 :

48 Recurrent bacterial Translocation Bacterial Translocation Bacterial infection LPS LPS LPS TNFα SIRS Monocyte deactivation CARS

49 Prognostic model model in patients with cirrhosis who were admitted with or developed a bacterial infection during hospitalization Parameter Estimate Standard Error OR OR 95 % CI P Value Intercept MELD ( ) < Albumin ( ) Heart rate ( ) Second infection ( ) JS. Bajaj et al. Hepatology 2012 (Epub ahead of print)

50 Actuarial probability of survival in patients with cirrhosis and ascites according to the Bact-DNA state and the MELD score Bact-DNA-ve Bact-DNA-ve Bact-DNA+ve Bact-DNA+ve P. Zapater et al. Hepatology 2008 ; 48 :

51 Headlines Prevalence Pathogenesis Pathophysiological consequences Clinical consequences Prevention

52 Aims in the prevention of Bacterial translocation to decrease the bacterial overgrowth to change the microbiome to reduce the intestinal permeability to manipulate the immune response

53 Primary prevention of spontaneous bacterial peritonitis (SBP) patients with cirrhosis and low protein ascitic level (15 g/l) and one of the following conditions: advanced liver failure (CTP 9 with total serum bilirubin 3 mg/dl) or impaired renal function (serum creatinine 1.2 mg/dl, BUN 25 mg/dl) or serum sodium level 130 mmol/l J. Fernandez et al. Gastroenterology 2007 ; 133 :

54 Probability of development of spontaneous bacterial peritonitis 100 (%) P < Placebo Norfloxacin days J. Fernandez et al. Gastroenterology 2007 ; 133 :

55 Probability of one year survival (%) Norfloxacin P < 0.01 Placebo days J. Fernandez et al. Gastroenterology 2007 ; 133 :

56 Probability of hepatorenal syndrome 100 (%) 80 P < Placebo Norfloxacin days J. Fernandez et al. Gastroenterology 2007 ; 133 :

57 Effects on norfloxacin on plasma endotoxins in patients with cirrhosis and ascites P < 0.05 (EU/ml) Before After B. Rasaratnam et al. Ann. Intern. Med ; 139 :

58 Norfloxacin and TNF- concentrations in 2 patients with multiple serum samples collected at inclusion (1) and at 15 days and 1, 2, 4, 7, 8, 9, and 10 months, respectively, after inclusion P. Zapater et al. Gastroenterology 2009;137:

59 Effects on norfloxacin on systemic vascular resistance in patients with cirrhosis and ascites P < 0.05 (units) Before After B. Rasaratnam et al. Ann. Intern. Med ; 139 :

60 Temporal relationship between intracellular levels of norfloxacin or trimethoprim/sulfamethoxazole and NF-B P. Zapater et al. Gastroenterology 2009;137:

61 Spontaneous bacterial peritonitis with septic shock sustained by Klebsiella pneumoniae in a patient with cirrhosis S. Piano et al. Eur. J. Gastroenterol. Hepatol ; 24 :

62 100 Bacterial translocation (BT) Rate of bacterial translocation in cirrhotic rats receiving Lactobacillus GG (LGG) or Milk (MILK) or norfloxacin sigle dose followed by LGG (NOR-LGG) or milk (NOR-MILK) Cecal colonization with Lactobacillus was achieved in 90% of treated rats 25 0 Control rats LGG-Cirrhotic rats MILK- Cirrhotic rats NOR-LGG Cirrhotic rats NOR-MILK Cirrhotic rats TM. Bauer et al. J. Hepatol ; 36 :

63 Cumulative probability of developing spontaneous bacterial peritonitis (SBP) in patients with cirrhosis receiving norfloxacin and probiotics and vs patients with cirrhosis receiving norfloxacin and placebo C. Pande et al. Eur. J. Gastroenterol. Hepatol ; 24 :

64 Effect of antibiotic, cisapride and placebo on small-intestinal bacterial overgrowth (SIBO) and oro-cecal transit time (OCTT) AM. Madrid et al. Am. J. Gastroenterol ; 96 :

65 Aims in the prevention of Bacterial translocation to decrease the bacterial overgrowth to change the microbiome to restore the intestinal mucosal barrier to manipulate the immune response

66 Prevention of spontaneous bacterial peritonitis by proponolol in non randomized control trials (RCTs) and in non randomized comparative studies M. Senzolo et al. Liver Int ; 29 :

67 Effect of spanchnic sympathetcomy (SE) on in vitro phagocytosis index of peritoneal polymorhonuclear lecocytes P < 0.01 P < Control rats Cintrol rats with SE Cirrhotic rats Cirrhotic rats with SE M. Worlicek et al. Gut 2010 ; 59 :

68 Aims in the prevention of Bacterial translocation to decrease the bacterial overgrowth to change the microbiome to restore the intestinal mucosal barrier to manipulate the immune response

69 Rate of bacterial translocation in rats with cirrhosis receiving anti-tnfα monoclonal antibody (anti-tnfα), placebo, or an IgG isotype control (IgG2a), 100 * = p < 0.05 P vs < 0.05 Group I Anti-TNF α Palcebo IgG2a R. Frances et al. J. Hepatol ; 46 :

70 Effects of pentoxifylline on intestinal bacterial overgrowth (IBO), bacterial translocation (BT) and spontaneous bacterial peritonitis (SBP) in rats with cirrhosis 100 P < 0.05 P < 0.05 P < Pentoxifylline reduced the level of malonyldialdeide in the cecal mucosa IBO BT SBP Control rats Pentoxifylline Norfloxacin Placebo F. Corradi et al. Dig. Liver Dis ; 44 :