MASSIMO PINZANI, MD, PhD, FRCPSheila Sherlock Chair of HepatologyUCL Institute for Liver and Digestive HealthRoyal Free Hospital, London, UK

m.pinzani@ucl.ac.uk

Complications of Cirrhosis: Update 2015

www.ucl.ac.uk/medicine/liver-and-digestive-health

Best of EASL is a program supported by an unrestrictedmedical education grant by Merck Sharp & Dohme,

Corp., a subsidiary of Merck & Co., Inc.

Best of EASL is a program supported by an unrestrictedmedical education grant by Merck Sharp & Dohme,

Corp., a subsidiary of Merck & Co., Inc.

Pathogenesis of Circulatory Abnormalitiesand Renal Failure in Cirrhosis

Gines P NEJM 2009

?

“DecompensatingEvent”

Stage 3

Bleeding

Stage 4First nonbleeding

decompensation

Stage 5

Seconddecompensation

Death orOLT

SEPSISRenalFailure

Hepatocellular Carcinoma

CompensatedCirrhosis

DecompensatedCirrhosis

Stage 1

Stage 2

No VaricesNo Ascites

VaricesNo Ascites

HVPG: 5-12 mm Hg

HVPG > 12 mm Hg

Modified from Arvaniti V. et al., Gastroenterology 2010; 139:1246-1256

Natural History of Cirrhosis: Mostly “Observational” !

Pathophysiology and complications of portalhypertension in cirrhosis

Tsochatzis, Bosch, Burroughs Lancet 2014

Ascites and HRS

Arroyo J Hepatol 2007

HepatorenalSyndrome

Natural history of ascites

Portal HypertensionNo ascites

UncomplicatedAscites

Refractory Ascites

<4% annual mortality

20% annual mortality

50% annual mortality

Survival in patients with ascites

Arroyo J Hepatol 2007

Propranolol: the “aspirin” of hepatologists

• Cheap

• Few contraindications

• Intolerance - use specialist nurses to improve compliance

- think of interferon (Tandon 2010)

• Universal applicability

• May affect outcomes other than bleeding

• Need a large multinational empirical RCT for survival

• Propranolol in combination:

- statin agents (Abraldes 2009)

- non absorbable antibiotics (Fernandez 2007)

b-blockers and prevention of ascites

83 patients with HVPG > 12 mmHg, b-blockers for primary prophylaxis of VB53 months mean-follow-up – 52 decompensated, 81% with ascites

Hernandez-Gea AmJGastro 2012

Reduced probability of ascites, refractory ascites and HRSIf HVPG reduction of ≥10%, only 19% developed ascites

Oesophageal varices in cirrhosis

• Present in 50% of patients at diagnosis

• Development/growth at 7%/year

• One year rate of first VB approximately 12%

• Six-week mortality of VB is 15-20%

• One year recurrence rate is 60%

Garcia-Tsao & Bosch NEJM 2010

Improved prognosis following first VB

McCormick Gut 2001

B-blockers decrease intestinal permeabilityand endotoxaemia irrespective of

haemodynamic response

Reiberger J Hepatol 2013

50 patients with cirrhosisIncreased intestinal permeability/bacterial translocation when HVPGImprovement with NSBBs irrespective of HVPG response

Early use of TIPS in varicealbleeding

Garcia-Pagan NEJM 2011

97%

50%

86%

61%

63 patientsChild-Pugh C or B with active bleedingEarly TIPS within 72h or standard treatment

?

“DecompensatingEvent”

Stage 3

Bleeding

Stage 4First nonbleeding

decompensation

Stage 5

Seconddecompensation

Death orOLT

SEPSISRenalFailure

Hepatocellular Carcinoma

CompensatedCirrhosis

DecompensatedCirrhosis

? ? ?

Compensated Cirrhosis a Clinical Stage withVery Limited Diagnostic Resources

Stage 1

Stage 2

No VaricesNo Ascites

VaricesNo Ascites

Modified from Arvaniti V. et al., Gastroenterology 2010; 139:1246-1256

YearsMonths

Cirrhosis Causes Structural and FunctionalChanges in the Mucosa of the Small Intestine

Op

tica

lden

sity

at5

40

nm

Bacterial adherence to BBM

Uri

nar

yex

cret

ion

of

DTP

A(%

)

Intestinal permeability

Control Cirrhosis

Ramachandran A. et al. Hepatology 2002Chiva M. et al. Eur J Gastroenterol Hepatol 2003Perez-Páramo M et al. Hepatology 2003Natarajan SK et al. Hepatology 2006

Functional abnormalities of the mucosa of thesmall intestine of rats with cirrhosis:

• oxidative stress, ↑ xanthine oxidase activity• lipid peroxidation of brush border membrane• ↑ sugar content of brush border membrane• abnormal intestinal transport

Control Cirrhosis

P<0.01

P<0.01

Changes in MicrobiotaBacterial Overgrowth

Decreased Bile Acids

Immunosuppression

Mesenteric Vein Congestion

Mucosal Injury (ETOH)

CIRRHOSIS

Obesity/OverweightHigh Fat Diet

Increased Pathogen-AssociatedMolecular Patterns “PAMPs”(i.e. LPS) in the portalcirculation

Zapater P et al. Hepatology 2008

weeks0 8 16 24 32 40

p=0.0040.2

0.4

0.6

0.8

1.0

0

High serum LBP 32.1%

Normal serum LBP 8.7%

Increased risk of spontaneous bacterialinfection in patients with cirrhosis and

high LBP

Increased risk of death, but notof SBP, in patients with

cirrhosis and bacterial DNA

days

Ove

rall

surv

ival

P=0.001

bactDNA (-)

bactDNA (+)

Different Outcome of Cirrhotic Patients withHigh LBP or Presence of bactDNA in Serum

Albillos A et al. Lancet 2004

AOCLF 1st monthBactDNA (+) 4/7BactDNA (-) 0/0

Cirrhosis-associated Immune DysfunctionSyndrome (CAIDS)

Altered albumin quality

Advanced Chronic Liver disease could be seen as theresult of an inflammatory syndrome in contradiction

with a simple hemodynamic disturbance

Dysbiosis in Chronic Liver Disease

• Dysbiosis and leaky gut characterizes natural historyand affects pathogenesis of liver diseases

• Type of dysbiosis is related to etiological cause ofliver diseases

• Dysbiosis has a main role in the development ofcirrhosis’ complications

Dysbiosis in Chronic Liver Disease

• Gut microbiota remodulation affects themanagement of the complications of cirrhosis

• Efficacy and safety• of systemic antibiotics for treatment and prevention of SBP• of lactulose and rifaximin for treatment and prevention of overt

and minimal HE

has been established in RCT and meta-analysis

• The potential of dysbiosis diagnosis and treatmentin liver diseases could go much beyond of SBP andencephalopathy treatment

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