Complications of Cirrhosis: Update 2015

Transcription

1 Complications of Cirrhosis: Update 2015 MASSIMO PINZANI, MD, PhD, FRCP Sheila Sherlock Chair of Hepatology UCL Institute for Liver and Digestive Health Royal Free Hospital, London, UK Best of EASL is a program supported by an unrestricted medical education grant by Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc.

2 Pathogenesis of Circulatory Abnormalities and Renal Failure in Cirrhosis Gines P NEJM 2009

3 Natural History of Cirrhosis: Mostly Observational! HVPG > 12 mm Hg HVPG: 5-12 mm Hg Stage 1 No Varices No Ascites Decompensating Event? Stage 3 Bleeding Stage 4 First non bleeding decompensation SEPSIS Renal Failure Death or OLT Stage 5 Varices No Ascites Second decompensation Stage 2 Hepatocellular Carcinoma Compensated Cirrhosis Decompensated Cirrhosis Modified from Arvaniti V. et al., Gastroenterology 2010; 139:

4 Pathophysiology and complications of portal hypertension in cirrhosis Tsochatzis, Bosch, Burroughs Lancet 2014

5 Ascites and HRS Arroyo J Hepatol 2007

6 Natural history of ascites Portal Hypertension No ascites <4% annual mortality Uncomplicated Ascites 20% annual mortality Refractory Ascites 50% annual mortality Hepatorenal Syndrome

7 Survival in patients with ascites Arroyo J Hepatol 2007

8 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)

9 b-blockers and prevention of ascites 83 patients with HVPG > 12 mmhg, b-blockers for primary prophylaxis of VB 53 months mean-follow-up 52 decompensated, 81% with ascites Reduced probability of ascites, refractory ascites and HRS If HVPG reduction of 10%, only 19% developed ascites Hernandez-Gea AmJGastro 2012

10 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

11 Improved prognosis following first VB McCormick Gut 2001

12 B-blockers decrease intestinal permeability and endotoxaemia irrespective of haemodynamic response 50 patients with cirrhosis Increased intestinal permeability/bacterial translocation when Improvement with NSBBs irrespective of HVPG response HVPG Reiberger J Hepatol 2013

13 Early use of TIPS in variceal bleeding 97% 50% 86% 61% 63 patients Child-Pugh C or B with active bleeding Early TIPS within 72h or standard treatment Garcia-Pagan NEJM 2011

14 Compensated Cirrhosis a Clinical Stage with Very Limited Diagnostic Resources Stage 1 No Varices No Ascites Decompensating Event? Stage 3 Bleeding Stage 4 First non bleeding decompensation SEPSIS Renal Failure Death or OLT Varices No Ascites Years Stage 5 Second decompensation Months Stage 2 Hepatocellular Carcinoma Compensated Cirrhosis??? Decompensated Cirrhosis Modified from Arvaniti V. et al., Gastroenterology 2010; 139:

15 Cirrhosis Causes Structural and Functional Changes in the Mucosa of the Small Intestine CIRRHOSIS Decreased Bile Acids Mucosal Injury (ETOH) Mesenteric Vein Congestion Immunosuppression Obesity/Overweight High Fat Diet Increased Pathogen-Associated Molecular Patterns PAMPs (i.e. LPS) in the portal circulation Functional abnormalities of the mucosa of the small 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 Ramachandran A. et al. Hepatology 2002 Chiva M. et al. Eur J Gastroenterol Hepatol 2003 Perez-Páramo M et al. Hepatology 2003 Natarajan SK et al. Hepatology 2006 P<0.01 Control Cirrhosis Bacterial adherence to BBM Optical density at 540 nm Changes in Microbiota Bacterial Overgrowth Urinary excretion of DTPA (%) Intestinal permeability P<0.01 Control Cirrhosis

16 Different Outcome of Cirrhotic Patients with High LBP or Presence of bactdna in Serum Increased risk of spontaneous bacterial infection in patients with cirrhosis and high LBP Increased risk of death, but not of SBP, in patients with cirrhosis and bacterial DNA bactdna (-) High serum LBP 32.1% 0. 2 p=0.004 Normal serum LBP 8.7% weeks Albillos A et al. Lancet 2004 Overall survival AOCLF 1 st month BactDNA (+) 4/7 BactDNA (-) 0/0 bactdna (+) days P=0.001 Zapater P et al. Hepatology 2008

17 Cirrhosis-associated Immune Dysfunction Syndrome (CAIDS) Altered albumin quality

18 Advanced Chronic Liver disease could be seen as the result of an inflammatory syndrome in contradiction with a simple hemodynamic disturbance

19 Dysbiosis in Chronic Liver Disease Dysbiosis and leaky gut characterizes natural history and affects pathogenesis of liver diseases Type of dysbiosis is related to etiological cause of liver diseases Dysbiosis has a main role in the development of cirrhosis complications

20 Dysbiosis in Chronic Liver Disease Gut microbiota remodulation affects the management 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 treatment in liver diseases could go much beyond of SBP and encephalopathy treatment

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