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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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Page 1: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Bacterial translocation in cirrhosis

P. AngeliUnit of Hepatic Emergencies and Liver Transplantation

Dept. of MedicineUniversityof Padova, Italy

[email protected]

AISF Monothematic Conference 2012The Gut-Liver axis: a bidiretional relation in health and disease

Bologna October 4-5th

Page 2: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Bacterial translocation (BT)

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 : 422-33

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0

25

50

75

100

Controls Cirrhotic rats with GBT Cirrhotic rats witho utGBT

Non ascites Ascites

Bacterial DNA fragments in mesenteric lymph nodes (MLNs) in cirrhotic rats according to positive cultures from MLNs

Bacterial translocation (BT)

M. Ubeda et al. Hepatology 2010 ; 52 : 2086-2095

%

Page 4: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

• Prevalence• Pathogenesis• Pathophysiological consequences• Clinical consequences• Prevention

Bacterial translocation (BT)

Headlines

Page 5: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

0

25

50

75

100

Controls Cirrhotic ptsCTP A

Cirrhotic ptsCTP B

Cirrhotic ptsCTP C

Cirrhotic ptswith SID

Positive cultures from mesenteric lymph nodes in cirrhotic patients (pts) according to the Child-Turcotte-Pugh (CTP) class and selective intestinal

decontamination (SID)

Bacterial translocation (BT)

I. Cicera et al. J. Hepatol. 2001 ; 34 : 32-37

(%)

P <0.05

Page 6: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Markers of bacterial translocationMarkers of bacterial translocation

Bact-DNA Bacterial footprints� Endotoxins (LPS)

� LPS binding protein

Bacterial translocation (BT)

Page 7: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Plasma levels of lipopolysaccharide (LPS) binding protein (LBP) in patients with cirrhosis and ascites

A. Albillos et al . Hepatology 2003 ; 37: 208-217

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4

8

12

16

20

24

Cirrhotics withascites

Cirrhotic withoutascites

Normal subjects

LBP

(µg/

ml) 42 %

Bacterial translocation (BT)

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Bact-DNA+vepatients

Bact-DNA-vepatients

63.4%36.6%

E. coli

E. fecium

K. pneumoniae

S. aureus

57.7%

7.7%

7.7%

26.9%

Prevalence of Bact-DNA in inpatients with cirrhosis and refcractory ascites

Bacterial tranlocation (BT)

P. Angeli et al . (AASLD Annual Meeting 2010)

Page 9: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

• Prevalence• Pathogenesis• Pathophysiological consequences• Clinical consequences• Prevention

Bacterial translocation (BT)

Headlines

Page 10: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

R. Wiest et al. Hepatology 2005 ; 41 : 422-433

Bacterial translocation (BT)

Mechanisms of bacterial translocation

Page 11: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

0

25

50

75

100

SBP No SBP

Small intestine bacterial overgrowth in cirrhotic patients according with the occurrence of SBP

CS. Chang et al. Hepatology 1998 ; 28 : 1187-1190

(%) P <0.01

Bacterial translocation (BT)

Page 12: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

0,0

0,5

1,0

1,5

2,0

Healthy controls Patients with cirrhosis

The Bifidobacteria/Enterobacteriaceae ratio in patients with decompensated cirrhosis

H. Lu et al. Micriobiol. Ecol. 2011 ; 61 : 693-703

P <0.01

Bacterial translocation (BT)

Page 13: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

F. Bert et al. J. Clin. Microbiol. 2010 : 48 : 2709-2714

24

4

48

24

0

20

40

60

Group A Group B1 Group B2 Group D

Phylogenetic groups of E. coli. in patients with cirrhosis and spontaneous bacterial peritotinitis and/or bacteremia

%

Bacterial translocation (BT)

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F. Bert et al. J. Clin. Microbiol. 2010 : 48 : 2709-2714

Bacterial translocation (BT)

Page 15: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

• 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

Factors contributing to the bacterial overgrowth in cirrhotic patients

Bacterial translocation (BT)

Page 16: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Drugs used only for a liver-related condition in hospitalized patients with cirrhosis in Spain

0

20

40

60

80

100

Diuretics Antiulcerdrugs

Laxatives Vitamin K Beta-blockers

Nitrates

On admission At discharge

%

MI. Lucena et al. Eur. J. Clin. Pharmacol. 2002 ; 58 : 435-440

Bacterial translocation (BT)

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0

20

40

60

80

100

SBP No SBP

Use of proton pump inhibitors (PPI) in patients with cirrhosis and spontaneous bacterial peritonitis

JS. Bajaj ,et al. Am. J. Gastroenterol. 2009 ; 104 :1130–1134

P <0.0001(%)

Bacterial translocation (BT)

Appropriate PPI use

Appropriate PPI use

Page 18: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

R. Wiest et al. Hepatology 2005 ; 41 : 422-433

Bacterial translocation (BT)

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

Page 19: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

R. Wiest et al. Hepatology 2005 ; 41 : 422-433

Bacterial translocation (BT)

Mechanisms of bacterial translocation

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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

(%) P <0.001

Bacterial translocation (BT)

Page 21: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

R. Wiest et al. Hepatology 2005 ; 41 : 422-433

Bacterial translocation (BT)

Mechanisms of bacterial translocation

Page 22: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

MLCK regulates ZO-1 exchange in vivo.

Yu D et al. PNAS 2010;107:8237-8241

©2010 by National Academy of Sciences

Schematic diagram of the molecular organization of epithelial tight junction

Bacterial translocation (BT)

Université de Genève 2011

Page 23: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

MLCK regulates ZO-1 exchange in vivo.

Yu D et al. PNAS 2010;107:8237-8241

©2010 by National Academy of Sciences

Bacterial translocation (BT)

DE. Fouts et al. J. Hepatol. 2012 ; 56 : 1283–1292

0,0

0,5

1,0

1,5

2,0

2,5

Baseline 1 Day

P <0.05

Occludin expression 1 day after ligation of the common bile duct (BDL)

Page 24: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

MLCK regulates ZO-1 exchange in vivo.

Yu D et al. PNAS 2010;107:8237-8241

©2010 by National Academy of Sciences

Schematic diagram of the molecular organization of epithelial tight junction

Bacterial translocation (BT)

Université de Genève 2011

Page 25: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

R. Wiest et al. Hepatology 2005 ; 41 : 422-433

Bacterial translocation (BT)

Mechanisms of bacterial translocation

Page 26: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Model for a role of Nod1 and Nod2 as cytosolic surveillance proteins of mucosal surfaces

Bacterial translocation (BT)

M. Chamaillard et al. Cell. Microbiol. 2003 5 : 581–592

Page 27: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Bacterial translocation (BT)

B. Appenrodt et al. Hepatology 2010 ; 51 : 1327-1333

Nucleotide-binding oligomerization domain containing2 (NOD2) Variants as a risk factors for spontaneous bacterial peritonitis

in patients with cirrhosis

Page 28: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

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. 2009 ; 43 : 182-190..

Page 29: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Model for a role of Nod1 and Nod2 as cytosolic surveillance proteins of mucosal surfaces

Bacterial translocation (BT)

M. Chamaillard et al. Cell. Microbiol. 2003 5 : 581–592

���� MLCK

Page 30: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

0,0

0,5

1,0

1,5

2,0

2,5

3,0

Control IFN TNF IFN + TNF

Myosin II regulatory light chainkinase (MLCK) phosphorylation

Bacterial translocation (BT)

F. Wang et al. Am. J. Pathol. 2005 ; 166 : 409-419

γγγγ γγγγ γγγγ αααα

P < 0.05

Page 31: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

0

50

100

150

200

250

Control IFN TNF IFN + TNF

Cultured intestinal epithelial cell permeability to 3kD fluorescein isothiocyanate-dextran exposed to IFN-γ followed by TNF-α

30 K

D D

extr

an fl

ux

Bacterial translocation (BT)

P < 0.001

F. Wang et al. Am. J. Pathol. 2005 ; 166 : 409-419

γγγγ γγγγ αααααααα

Page 32: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

• Prevalence• Pathogenesis• Pathophysiological consequences• Clinical consequences• Prevention

Bacterial translocation (BT)

Headlines

Page 33: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Increasing rate of BT

Bacterial translocation (BT)

Endotoxins and proinflammatory citokines

Page 34: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

• Bacterial infections

• Cardiovascular dysfunction• Renal failure• Hepatic encephalophaty

Bacterial translocation (BT)

Bacterial translocation in cirrhosis: clinical consequences

Page 35: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Bacterial translocation (BT)

↑↑↑↑ TNFα

SIRS

Bacterial infection

Viable Bacteria Translocation

↑↑↑↑ LPS

Bacterial translocation in cirrhosis: consequences

Page 36: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

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)

Page 37: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

↑↑↑↑ LPS

Bacterial translocation (BT)

↑↑↑↑ TNFα

SIRS

Bacterial infection

Bacterial fragments Translocation

↑↑↑↑ LPS

Bacterial translocation in cirrhosis: consequences

Page 38: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

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.

Page 39: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Molecular translocation persists during i.v. antibiotic tretament of SBP episodes

R. Frances et al . Hepatology 2008 ; 47 : 978-985

Bacterial translocation (BT)

Page 40: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

• Bacterial infections

• Cardiovascular dysfunction• Renal failure• Hepatic encephalophaty

Bacterial translocation (BT)

Bacterial translocation in cirrhosis: clinical consequences

Page 41: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Event Bact-DNA+ve Bact-DNA-ve p value (n= 23) (n= 14)

All complications 96% 64% < 0.05HRS 1 26% 0 % < 0.05Death 46% 14% < 0.05

P. Angeli et al. (AASLD Annual Meeting 2010)

Six month follow up of patients with cirrhosis and refractory ascites according to the detection of Bact-DNA in ascites

Six month follow up of patients with cirrhosis and refractory ascites according to the detection of Bact-DNA in ascites

Bacterial translocation (BT)

Page 42: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Further derangement of

Systemic heamodynamicsFibrosis progression in the liver

dnd increase in portal pressure

Bacterial translocation (BT)

Endotoxins and proinflammatory citokines

Organ failure(s)

Page 43: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Bacterial translocation (BT)

N. Shah et al. Journal of Hepatology 2012 vol. 56 j 1047–1053

TLR4 expression in the Bile duct ligated and in the BDL + LPS group

Page 44: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Bacterial translocation (BT)

N. Shah et al. Journal of Hepatology 2012 vol. 56 j 1047–1053

Methamine silver staining of the kidney in the BDL group and in the BDL group administered LPS (BDL+LPS group)

Page 45: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

• Bacterial infections

• Cardiovascular dysfunction• Renal failure• Hepatic encephalophaty

Bacterial translocation (BT)

Bacterial translocation in cirrhosis: clinical consequences

Page 46: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

0

500

1000

1500

2000

2500

3000

Control rats Cirrhotic ratsBactDNA-ve and

GBT-ve

Cirrhotic ratsBactDNA+veand GBT-ve

Cirrhotic ratsGBT+ve

Bacterial translocation (BT)

L. Munoz et al. Hepatology 2012 (Epub ahead of print)

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)

Page 47: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Bcterial translocation (BT)

Schematic representation of the “in vitro” model of functional monocyte decativation

GA. Antoniades et al. J. Hepatol. 2008 ; 49 : 945-861

Page 48: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

↑↑↑↑ LPS

Recurrent bacterial Translocation

↑↑↑↑ LPS

Monocyte deactivation

CARS

Bacterial translocation (BT)

↑↑↑↑ TNFα

SIRS

Bacterial infection

Bacterial Translocation

↑↑↑↑ LPS

Page 49: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Bacterial translocation (BT)

Parameter EstimateStandard

ErrorOR OR 95 % CI P Value

Intercept -4.9689 1.5511

MELD 0.1169 0.0281 1.124 (1.064-1.188) < 0.0001

Albumin -0.6863 0.3341 0.503 (0.262-0.069) 0.0399

Heart rate 0.0279 0.0120 1.028 (1.004-1.053) 0.0202

Second infection 1.4852 0.4022 4.4416 (2.007-9.713) 0.0002

JS. Bajaj et al. Hepatology 2012 (Epub ahead of print)

Prognostic model model in patients with cirrhosis who were admitted with or developed a bacterial infection during hospitalization

Page 50: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

Actuarial probability of survival in patients with cirrhosis and ascites according to the Bact-DNA state and the MELD score

P. Zapater et al. Hepatology 2008 ; 48 : 1924-1931

Bacterial translocation (BT)

Bact-DNA+ve

Bact-DNA-ve

Bact-DNA+ve

Bact-DNA-ve

Page 51: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

• Prevalence• Pathogenesis• Pathophysiological consequences• Clinical consequences• Prevention

Bacterial translocation (BT)

Headlines

Page 52: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

• to decrease the bacterialovergrowth

• to change the microbiome• to reduce the intestinalpermeability• to manipulate the immune response

Bacterial translocation (BT)

Aims in the prevention of Bacterial translocation

Page 53: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

• 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)

Page 54: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

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)

Page 55: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

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)

Page 56: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

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)

Page 57: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

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)

Page 58: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

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

Page 59: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

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)

Page 60: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

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

Page 61: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

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)

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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

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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

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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)

Page 65: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

• 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

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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)

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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

Page 68: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

• 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

Page 69: Bacterial translocation in cirrhosis - AISF · Bacterial translocation in cirrhosis P. Angeli Unit of Hepatic Emergencies and Liver Transplantation ... Laxatives Vitamin K Beta-blockers

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

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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