MANAGING END STAGE LIVER DISEASE IN RESOURCE LIMITED SETTINGS

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1 MANAGING END STAGE LIVER DISEASE IN RESOURCE LIMITED SETTINGS Mark W. Sonderup Division of Hepatology and Liver Laboratory Department of Medicine University of Cape Town & Groote Schuur Hospital

2 Cirrhosis.. End stage of any chronic liver disease Characterized histologically by regenerative nodules surrounded by fibrous tissue - is technically a histological diagnosis However, in patients with chronic liver disease the presence of various clinical features suggest cirrhosis Non-invasive assessment can reliably replace biopsy Clinically there are two distinct phases of cirrhosis: -> Compensated -> Decompensated

3 Diagnostic Algorithm Yes Patient with chronic liver disease and any of the following: Variceal hemorrhage Ascites Hepatic encephalopathy No Physical findings: Laboratory findings: Non-invasive tests Enlarged left hepatic lobe Thrombocytopenia APRI, FIB-4 Splenomegaly Impaired synthetic liver function VCTE (Fibroscan) Stigma of chronic liver disease Yes No Yes Liver biopsy not necessary for the diagnosis of cirrhosis Radiological findings: Small nodular/irregular liver Intra-abdominal collaterals Ascites Splenomegaly No Liver biopsy

4 Natural History of Chronic Liver Disease Chronic liver disease Compensated cirrhosis Decompensated cirrhosis Death e.g. hep B/C; iron, alcohol etc

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7 Management of Compensated Cirrhosis Chronic liver disease Compensated cirrhosis Diagnosis: Liver biopsy Clinical/Radiology/Bloods/Non-invasive Decompensated cirrhosis Death Screen for varices (OGD): Orthotopic liver transplant (OLT) Screen for HCC: α-fp; Ultrasound every 6 months? treatment of underlying problem Measures to stop alcohol Hep A and B vaccination

8 LT-Free Survival (%) HBV Therapy Reduces Risk of Disease Progression Prospective cohort study in pts with HBV and first-onset complications of decompensated cirrhosis (N = 707) treated predominantly with lamivudine (n = 203) or entecavir (n = 198) Bonferroni-adjusted P < Months Treated, responder (n = 245) Treated, nonresponder* (n = 178) Untreated (n = 284) Antiviral therapy improved transplant-free survival over mean follow-up of 49 mos * (P =.0098 vs untreated) Nonresponders included pts with HBV rebound or genotypic resistance, primary nonresponse, NE due to early event (death, LT, LTFU). Jang JW, et al. Hepatology. 2015;61:

9 ETV, n=57, median FU 280 weeks TDF, n=348 Cirrhosis regression: 71/96 (74%) Progression to cirrhosis of non-cirrhotics : 3/252 (1,2%)

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11 Percent HCV Treatment Improves Health Advanced fibrosis Multicenter study [1] 5 hospitals (Europe, Canada) 530 pts with HCV IFN regimens Advanced fibrosis or cirrhosis Median follow-up: 8.4 yrs Early-stage disease Extra-hepatic manifestations [2] Health-related quality of life [3] All cause mortality Liver-related mortality or transplant 5.1 HCC 10-Yr Cumulative Incidence [1] 21.8 SVR No SVR 1. van der Meer AJ, et al. JAMA. 2012;308: van der Meer AJ. Expert Rev Gastroenterol Hepatol. 2015;9: Younossi Z, et al. Clin Gastroenterol Hepatol. 2014;12:

12 Survival HCC-Free Survival SVR With DAA Therapy: Mortality and HCC Risk Patients with HCV infection, FIB-4 > 3.25 in VA HCV Clinical Case Registry (N = 15,059) SVR with DAA therapy significantly lowered all-cause mortality and incident HCC 1 All-Cause Mortality SVR 1 Incident HCC SVR 0,9 0,8 0,7 79% reduction with SVR P <.001 No SVR 0,9 0,8 0,7 84% reduction with SVR P <.001 No SVR 0,6 0,6 0,5 0, Time Since DAA EOT (Years) Time Since DAA EOT (Years) Backus LI, et al. Hepatology. 2017

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15 Pathophysiology of bacterial translocation and bacteremias in cirrhosis

16 PAMP s: pathogen associated molecular patterns e.g.

17 Pathophysiology of Ascites Formation : splanchnic and systemic vasodilation

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20 Prophylactic Antibiotics Improve Outcomes in Cirrhotic Patients with GI Hemorrhage Control Antibiotic Absolute (n=270) (n=264) difference (95% CI) Infection 45% 14% -32% (-42 to 23) SBP / Bacteremia 27% 8% -18% (-26 to 11) Death 24% 15% -9% (-15 to 3) Bernard et al., Hepatology 1999; 29:1655

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23 Bacterial infections in cirrhosis Incidence of infection and severity in cirrhosis is greater than general population Infection with multi-resistant organisms is greater in cirrhosis and associated with higher mortality rates Infections provoke Acute on Chronic Liver Failure Diagnostic and treatment delays enhances mortality Jalan et al. J Hep Jun 60(6). 1310

24 Cirrhosis and portal HPT Vascular resistance to portal blood flow Portal pressure Splanchnic arteriolar resistance Portal blood inflow Varices

25 Varices Increase in Diameter Progressively No varices Small varices Large varices 7-8%/year 7-8%/year Merli et al. J Hepatol 2003;38:266

26 Large Varices Are More Likely To Rupture No Varices Small Varices p<0.01 * % Patients without bleeding 50 Large Varices * * 25 Six-week mortality of VB is 15-20% year probability of first bleed: Small varices: 7% Large varices: 30% Time (months) One year recurrence rate is 60% * Merli et al., Hepatol 2003; 38:266, ** Conn et al., Hepatology 1991; 13:902

27 Mortality from 1 st variceal bleed has improved McCormick. Gut Nov;49(5):682-5.

28 B-blockers still recommended as 1 st line however local factors determine approach Khuroo et al. APT

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30 Does everyone need to be scoped of OV surveillance? Can we risk stratify patients who need screening? If so, how? Can Transient Elastography (Fibroscan R ) help us select patients?

31 Stiffness (kpa) Liver Stiffness y = ,037 r 2 = 0,61 p < 0,0001 PH scarcely related to Fibrosis: CIRRHOSIS BECOMES A SYSTEMIC DISEASE PH related to Fibrosis HVPG (mmhg) Vizzutti F et al., Hepatology 2007; 45:

32 Diagnostic performance of transient elastography for the detection of clinically significant portal hypertension (HVPG 10 mm Hg) Authors Patients (n) Etiologies Study design Prevalence of Cinically Significant Portal hypertension Cut-offs HVPG 10 mm Hg (kpa) AUC Se (%) Sp (%) PPV (%) NPV (%) +LR -LR Carrion et al. (35) Vizzutti et al. (36) HCV-LT HCV Prospective monocentric Prospective monocentric 21% 77% 8.7* ** Sanchez-Condé et al. (39) Lemoine et al. (38) Bureau et al. (37) HIV-HCV HCV Alcohol CLD Prospective monocentric Retrospective monocentric Prospective monocentric 74% 77% 83% 51% ** * Hepatic Venous Pressure Gradient (HVPG) 6 mm Hg; ** severe portal hypertension HVPG 12 mm Hg AUC: area under ROC curve; Se sensitivity; Sp specificity; +LR positive likelihood ratio; -LR negative likelihood ratio; HCV chronic hepatitis C; HCV-LT Liver transplant for hepatitis C; CLD chronic liver diseases; Castera L, Pinzani M, Bosch J, J Hepatology 2012

33 BAVENO VI Screening and surveillance: Invasive and non-invasive The introduction of transient elastography (TE) in clinical practice has allowed the early identification of patients with chronic liver disease (CLD) at risk of developing clinically significant portal hypertension (CSPH) (1b;A). Identification of patients with cacld who can safely avoid screening endoscopy (new) Patients with a liver stiffness <20 kpa and with a platelet count >150,000 have a very low risk (<5%) of having varices requiring treatment, and can avoid screening endoscopy (1b;A). AASLD guidance 2016

34 The Spleen in the Assessment of Advanced Chronic Liver Disease INCREASE IN SPLEEN STIFFNESS?? Congestion Hypertrophy and Hyperplasia Fibrosis

35 Measurement of Spleen Stiffness by Fibroscan 1. Sufficient intercostal space width 2. - Splenic parenchymal thickness > 4 cm (by US) 3. Success rate > 60% and IQR < 30% of median value 4. Intra-observer reproducibility 96%, inter-observer reproducibility 94% 5. Probe upper limit 75 kpa

36 HVPG (mm Hg) HVPG (mm Hg) Spleen Stiffness (SS), a Diagnostic Parameter in Cirrhosis Colecchia A. et al., Gastroenterology 2012 ; 143(3): P = R² = 0,70 30 P = R 2 = 0, Compensated Cirrhosis Liver Stiffness (kpa) Spleen Stiffness (kpa) Esophageal Varices: NO Esophageal Varices: YES

37 Liver and Spleen Stiffness for the Prediction of the Presence of Esophageal Varices Colecchia A. et al., Gastroenterology 2012 ; 143(3): EV: NO EV: YES EV: NO EV: YES

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39 Using Beta Blockers: Practical Tips Monitor Resting Heart Rate, BP Long-acting agents (eg. Propranolol LA) preferred - Administer in the evening If non Long Acting BD or TDS (low doses! e.g mg per dose to start with) Start low and increment to target Target: Resting heart rate beats per minute/25% reduction in heart rate/maximal tolerated dose Ideal titrate to HVPG<12mmHg

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41 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

42 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 HVPGreductionof 10%,only19%developedascites Hernandez-Gea AmJGastro 2012

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44 Propranolol: the aspirin of hepatologists? Cheap Universal availability May affect outcomes other than bleeding e.g. Portal Gastropathy Propranolol in combination: - statin agents (Abraldes 2009) - non absorbable antibiotics (Fernandez 2007)

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49 J Hepatol Mar;64(3):574-82

50 Beta blockers in cirrhosis: The window re-opens.

51 Management of Ascites

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53 Cirrhosis Intrahepatic resistance Arteriolar resistance (vasodilation) Sinusoidal pressure (HVPG mmhg) Na restriction Effective arterial blood volume Ascites LVP Sodium and water retention Diuretics Activation of neuro-humoral systems (renin, angiotensin, aldosterone)

54 Dietary Na + restriction

55 Calculating the Na + balance Calculating the Na + balance

56 Diuretic Therapy Diuretic Therapy Angeli et al. GUT 2010

57 Diuretic Diuretic Therapy Therapy Angeli et al. GUT 2010

58 Diuretics best to initiate with combination of spironolactone and furosemide spironolactone titrated to maximum 400mg/day furosemide titrated to maximum 160mg/day start low and monitor response (weight), renal function, K + taper doses when ascites free

59 Large Volume Paracentesis best approach for tense ascites does not address underlying issue viz. salt/h 2 O retention

60 Large Volume Paracentesis

61 Gines et al Gastroenterology 1998.

62 Post Paracentesis Circulatory Dysfunction Definition Increase in >50% PRA from pre-paracentesis level to a maximum on day of >4ng/ml/hr Incidence 27% Associated with: 20% AKI Decreased survival HRS

63 Gines et al Gastroenterology 1998.

64 Use of albumin with LVP how much?

65 Intrahepatic resistance Cirrhosis worsening liver disease Arteriolar resistance (vasodilation) Sinusoidal pressure Effective arterial blood volume Refractory Ascites Sodium and water retention Activation of neurohumoral systems

66 Refractory Ascites International Ascites Club criteria Diuretic resistant (20%) failure to lose at least 1.5kg/wk on: - 400mg spironolactone - 160mg furosemide Diuretic intractable (80%) failure to lose weight due to the inability to use effective doses of diuretics because of intolerance or SE s

67 Management of refractory ascites

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69 Patients who benefited the most with albumin: Creatinine > 88umol/L (>1mg/dl) Bilirubin > 68umol/L (>4mg/dl)

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73 Sarcopaenia

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76 Hepatic Encephalopathy

77 Pathogenesis of Hepatic Encephalopathy Toxins Failure to metabolise NH 3 NH 3 shunting Bacterial action Protein load GABA-BDZ receptors

78 Precipitants of hepatic encephalopathy Protein excess GI Bleeds Sedative/ Hypnotic drugs TIPSS Diuretics Temperature K + Dehydration Renal failure Infections

79 Treatment of Hepatic Encephalopathy Identify and treat precipitating factor Infection GI hemorrhage Dehydration Sedatives Constipation Lactulose (adjust to 2-3 bowel movements/day) Protein restriction, short-term

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81 Lactulose as the Gold Standard for Rx of Encephalopathy Systematic review of randomised trials Bodil Als-Nielsen et al. BMJ 2004

82 Rifaximin in the treatment of HE

83 Rifaximin reduced the risk of breakthrough HE by 58% vs. placebo Bass et al. NEJM 2010;362:

84 Rifaximin reduced the risk of HE related hospitalization by 50% vs. placebo

85 Summary : Cirrhosis Management in Resource limited Benefits associated with survival settings Treat underlying cause of cirrhosis!!! Albumin with SBP and post LVP (if available, otherwise crystalloid) Antibiotic prophylaxis post GI bleed β-blocker value extends beyond OV prophylaxis Don t stop statins Nutrition!