Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation Dept. of Medicine Universityof Padova, Italy [email protected]AISF Monothematic Conference 2012 The Gut-Liver axis: a bidiretional relation in health and disease Bologna October 4-5th
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Bacterial translocation in cirrhosis
P. AngeliUnit of Hepatic Emergencies and Liver Transplantation
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 : 422-433
Bacterial translocation (BT)
Mechanisms of bacterial translocation
0
10
20
30
40
Control subjectcs Patients with cirrhosis
Percentage of urine excretion of a marker of integrity of mucosal barrier in cirrhotic patients
C. Ersoz et al. Eur. J. Gastroenterol. Hepatol. 1999 ; 11 : 409-412
Bacterial translocation in cirrhosis: clinical consequences
Bacterial translocation (BT)
↑↑↑↑ TNFα
SIRS
Bacterial infection
Viable Bacteria Translocation
↑↑↑↑ LPS
Bacterial translocation in cirrhosis: consequences
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 : 1608-1610
Bacterial translocation (BT)
↑↑↑↑ LPS
Bacterial translocation (BT)
↑↑↑↑ TNFα
SIRS
Bacterial infection
Bacterial fragments Translocation
↑↑↑↑ LPS
Bacterial translocation in cirrhosis: consequences
�
0
100
200
300
400
500
Serum TNF Serum IFN
Bact-DNA-ve Bact-DNA+ve SBP
R. Frances et al . Hepatology 2008 ; 47 : 978-985
Tumor necrosis factor α (TNFα) and Interferon γγγγ (INF γγγγlevels in cirrhotic patients with ascites
Bacterial translocation (BT)
(pg/
ml)
αααα γγγγ
N.S.N.S.
Molecular translocation persists during i.v. antibiotic tretament of SBP episodes
• to change the microbiome• to reduce the intestinalpermeability• to manipulate the immune response
Bacterial translocation (BT)
Aims in the prevention of Bacterial translocation
• patients with cirrhosis and low protein asciticlevel (15 g/l)
Primary prevention of spontaneous bacterial peritonitis (SBP)
and one of the following conditions:
• advanced liver failure (CTP ≥ 9 with total serumbilirubin ≥ 3 mg/dl)
or
• impaired renal function (serum creatinine ≥ 1.2mg/dl, BUN ≥ 25 mg/dl)
or
• serumsodiumlevel ≤ 130 mmol/l
J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824
Bacterial translocation (BT)
0
20
40
60
80
100
(%)
Probability of development of spontaneous bacterial peritonitis
Norfloxacin
PlaceboP < 0.001
J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824
100 200 days300 400
Bacterial translocation (BT)
0
20
40
60
80
100(%)
Probability of one year survival
100
Norfloxacin
Placebo
P < 0.01
200 days
J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824
300 400
Bacterial translocation (BT)
0
20
40
60
80
100
(%)
Probability of hepatorenal syndrome
100
Norfloxacin
Placebo
P < 0.05
200 days
J. Fernandez et al. Gastroenterology 2007 ; 133 : 818-824
300 400
Bacterial translocation (BT)
Effects on norfloxacin on plasma endotoxins in patients with cirrhosis and ascites
0
4
8
12
16
Before After
(EU
/ml)
P < 0.05
B. Rasaratnam et al. Ann. Intern. Med. 2003 ; 139 : 186-193
Bacterial translocation (BT)
Bacterial translocation (BT)
P. Zapater et al. Gastroenterology 2009;137:1669–1679
Norfloxacin and TNF- concentrations in 2 patientswith multiple serum samples collected at inclusion (1) and at 15
days and 1, 2, 4, 7, 8, 9, and 10 months, respectively, after inclusion
Effects on norfloxacin on systemic vascular resistance in patients with cirrhosis and ascites
5
10
15
20
25
30
Before After
(uni
ts)
P < 0.05
B. Rasaratnam et al. Ann. Intern. Med. 2003 ; 139 : 186-193
Bacterial translocation (BT)
Bacterial translocation (BT)
P. Zapater et al. Gastroenterology 2009;137:1669–1679
Temporal relationship between intracellular levels of norfloxacin or trimethoprim/sulfamethoxazole and NF-B
Spontaneous bacterial peritonitis with septic shock sustained by Klebsiella pneumoniae in a patient with cirrhosis
S. Piano et al. Eur. J. Gastroenterol. Hepatol. 2012 ; 24 : 1234–1237
Bacterial translocation (BT)
0
25
50
75
100
Control rats LGG-Cirrhoticrats
MILK-Cirrhotic rats
NOR-LGGCirrhotic rats
NOR-MILKCirrhotic rats
Bacterial translocation (BT)
TM. Bauer et al. J. Hepatol. 2002 ; 36 : 501–506
Rate of bacterial translocation in cirrhotic rats receiving Lactobacillus GG (LGG) or Milk (MILK) or norfloxacin sigle dose f ollowed by LGG
(NOR-LGG) or milk (NOR-MILK)
Cecal colonization with Lactobacillus was achieved in 90% of treated rats
Bacterial translocation (BT)
C. Pande et al. Eur. J. Gastroenterol. Hepatol.. 2012 ; 24 : 831–839
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
Bacterial translocation (BT)
AM. Madrid et al. Am. J. Gastroenterol. 2001 ; 96 : 1251-1255
Effect of antibiotic, cisapride and placebo on small-intestinal bacterial overgrowth (SIBO) and oro-cecal transit time (OCTT)
• to decrease the bacterialovergrowth
• to change the microbiome• to restore the intestinalmucosal barrier• to manipulate the immune response
Bacterial translocation (BT)
Aims in the prevention of Bacterial translocation
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. 2009 ; 29 : 1189-19993
Bacterial translocation (BT)
0
10
20
30
40
Control rats Cintrol rats withSE
Cirrhotic rats Cirrhotic ratswith SE
Bacterial translocation (BT)
M. Worlicek et al. Gut 2010 ; 59 : 1127-1134
Effect of spanchnic sympathetcomy (SE) on in vitro phagocytosis index of peritoneal polymorhonuclear lecocytes
P < 0.01
P < 0.01
• to decrease the bacterialovergrowth
• to change the microbiome• to restore the intestinalmucosal barrier• to manipulate the immune response
Bacterial translocation (BT)
Aims in the prevention of Bacterial translocation
Rate of bacterial translocation in rats with cirrhosis receiving anti-TNFααααmonoclonal antibody (anti-TNFαααα), placebo, or an IgG isotype control(IgG2a),
R. Frances et al. J. Hepatol. 2007 ; 46 : 797–803
* = p < 0.05 vs Group I
Bacterial translocation (BT)
0
25
50
75
100
Anti-TNF Palcebo IgG2a
P < 0.05
αααα
0
25
50
75
100
IBO BT SBP
Control rats Pentoxifylline Norfloxacin Placebo
F. Corradi et al . Dig. Liver Dis. 2012 ; 44 : 239-244
Effects of pentoxifylline on intestinal bacterial overgrowth (IBO), bacterial translocation (BT) and spontaneous bacterial peritonitis
(SBP) in rats with cirrhosis
Bacterial translocation (BT)
P < 0.05 P < 0.05 P < 0.05
Pentoxifylline reduced the level of malonyldialdeide in the cecal mucosa