Managing the Cirrhotic Patient

Managing the Cirrhotic Patient
End Stage Liver Disease and HCC Dominic Ray-Chaudhuri New Zealand Liver Transplant Unit

Disclaimer Please note:
The presentations express the views and opinions of the presenter which are based on the latest information and data available at the time of preparation and are not necessarily endorsed by Gilead Any patient cases and treatment options referred to are in the context of contemporary knowledge and medical practice in the field

Hepatitis B and risk of development of cirrhosis
Lifetime risk of cirrhosis 10-20% Liaw et al, Hepatology 1988;8:

Long-term Lamivudine in Cirrhosis Prevention of Decompensation
651 patients in Australia, NZ and Asia with HBV-cirrhosis received Lamivudine for 3-5 years 21% Placebo (n=215) Cumulative rate of disease progression P<0.001 9% Lamivudine (n=436) Time to disease progression (months) Time (months) Liaw, NEJM,2004 4

Natural History of Cirrhosis
Compensated cirrhosis Asymptomatic, with or without gastric or oesophageal varices Decompensated cirrhosis The development of symptomatic complications of cirrhosis: jaundice, ascites, variceal haemorrhage or hepatic encephalopathy Increased risk of development of hepatocellular carcinoma

Stages of cirrhosis: 5 year outcomes
Compensated Cirrhosis Decompensated cirrhosis D’Amico et al, Aliment Pharmacol Ther 2014;39:

Hepatitis B cirrhosis - prognosis
Hepatitis B sAg +ve cirrhosis: Survival at 1yr 92%, 3yr 79%, 5yr 71% Hepatitis B eAg +ve: 5yr survival 72% eAg –ve: 5yr survival 97% Compensated cirrhosis: 5yr survival 84% Decompensated cirrhosis: 5yr survival 14% De Jongh et al, Gastro 1992; 103: Decompensated = ascites, jaundice, encephalopathy with or without variceal bleeding

Why has decompensation occurred
Treatment naïve patient Viral breakthrough - non-compliance - viral resistance Development of hepatocellular carcinoma Progression due to non-hepatitis B liver disease – alcohol - NASH - co-infection

Management of End Stage Liver Disease
Management of process causing liver damage - treatment of hepatitis B - management of non-hepatitis B liver disease Management of complications - Ascites - Variceal bleeding - Hepatic encephalopathy - Spontaneous bacterial peritontis - Hepatorenal syndrome Consider if possible transplant candidate

Anti-viral Therapy in Decompensated Hepatitis B
Antiviral therapy improves transplant-free survival and liver synthetic function, reduces need for transplant CPT reduced by ≥ 3pts in 61% treated patients, none of controls OLT in 34.8% of treated patients, 73.9% of controls No deaths in treated group, 6 in control group Lamivudine CPT greater than or equal to 10 in all patients Yao et al, Hepatology 2001; 34:

Entecavir Baseline: mean CPT 8.1, mean MELD 11.5 After 12/12: ≥2 point decline in CPT Mean CPT 6.6, mean MELD 8.8 65.5% achieved CPT class A In responders, 55.6% improved in 3/12, 74.1% in 6/12 Shim et al, J Hepatol 2010; 52:

Tenofovir Entecavir Baseline MELD 11 10.5 CPT 7 Viral load (log cpml) 5.7 5.93 ALT (iu/ml) 48 52 Week 48 Δ in MELD -2 CPT≥ 2 points (%) 26 42 HBV DNA < 400cpml (%) 70.5 72.7 ALT normal (%) 56.8 54.5 Liaw et al, Hepatology 2011; 53: 62-72

Lamivudine Adefovir Tenofovir
Liver transplantation for Hepatitis B Oral antivirals have changed listing indication Acute/ACLF 3 4 6 5 HCC 15 14 3 6 13 12 Decomp Lamivudine Adefovir Tenofovir 15 14 12 10 Number of Transplants 5 2 4 1 3 1997/8 1999/2000 2001/2 2003/4 2005/6 2007/8 2009/10 2011/12 2013/14

Entecavir or Tenofovir in Decompensated Hepatitis B?
Both effective Both high barrier to viral resistance Lactic acidosis with entecavir? 5 patients, all cirrhotic lactic acidosis 4 to 240 days after starting entecavir MELD>20 in all Lactic acidosis resolved 3-5 days after cessation Entecavir and tenofovir associated with similar rates of viral suppression, complete viral suppression in slightly higher numbers treated with tenofovir. No resistance to tenofovir, but very low rates with entecavir. Severe lactic acidosis in 3 patients, 1 patient died Lange et al, Hepatology 2009; 50:

Ascites Why treat ascites: Patient discomfort
Adverse effect on energy balance Risk of spontaneous bacterial peritonitis Diet: Na+ restriction: <88meq (2000mg/day) Diuretics: Spironolactone, up to 400mg/d Frusemide, up to 160mg/d (Amiloride) Potential problems: hyponatraemia hypokalaemia renal impairment diuretic resistance

Ascites Refractory ascites:
Midodrine, in addition to standard medical treatment, superior to standard medical treatment alone in control of ascites Singh et al, Am. J. Gastr., 2013; 108: 560-7 Large volume paracentesis: albumin replacement – 8g per litre drained. Midodrine alpha-1-blocker: vasoconstriction in splanchnic bed and vasodilatation in renal vasculature.

Ascites Transjugular Intrahepatic Portosystemic Shunt (TIPS)
Contraindicated if history of encephalopathy, severe liver failure

Varices Mainly oesophageal and gastric, less frequently rectal, duodenal Endoscopic grading of oesophageal varices

Varices Management - varices only bleed if portal pressure >12mmHg
- Prophylaxis: non-selective -blockers (propranolol or nadolol)  splanchnic vasoconstriction ideally directly confirm  in portal pressure increase to HR 55/min or max tolerated dose Other benefits: reduce risk of spontaneous bacterial peritonitis ?-blockers not beneficial in all patients with varices

Variceal bleeding Medical management: Terlipressin (vasopressin agonist) 2mg stat, 1mg 6 hourly  splachnic vasoconstriction   portal pressure antibiotics (cefuroxime)  reduce risk of re-bleed Endoscopic management: Banding Gluing

Hepatic encephalopathy
- In chronic liver disease, loss of hepatocellular function AND portosystemic shunting  blood ‘bypassing’ liver - Precipitants: Constipation, sepsis, drugs (opiates, benzodiazepines), electrolyte disturbance, GI bleeding - 1st line treatment: Lactulose, aim for BO 3-4x/24hrs - Chronic or recurrent encephalopathy despite lactulose: Rifaximin pts with recurrent HE despite lactulose - randomised to Rifaximin or placebo - breakthrough HE: Rifaximin group 22% Placebo group 46% Bass et al, NEJM, 2010; 362:

Spontaneous Bacterial Peritonitis
Ascitic fluid infection without evident intra-abdominal, surgically-treatable cause Very uncommon without clinically apparent ascites In-hospital mortality after 1st episode 10-50% 1yr mortality after 1st episode 31-93% Risk of SBP correlates with ascitic fluid protein content: protein >15g/l incidence <1% < 10g/l incidence 27-41% Proton pump inhibitors may increase risk, β-blockers likely reduce risk SBP most common infection in patients with cirrhosis

Clinical features May have no or vague abdominal symptoms Frequently presents with encephalopathy or renal dysfunction Diagnosis Diagnostic ascitic tap: WCC>250/mm3, mainly polymorphs Most frequent organisms: E.coli, Klebsiella pneumoniae Treatment Antibiotics (Cefuroxime), IV albumin (20%) All patients should receive prophylaxis after 1st episode

Hepatorenal Syndrome Renal failure in patients with advanced chronic liver disease with portal hypertension and ascites with no other apparent cause (euvolaemic, not shocked, no nephrotoxic drugs, no urinary tract obstruction) Activation of renin-angiotensin-aldosterone system amd sympathetic nervous system  renal vasoconstriction Kidneys histologically normal Type 1 – rapid, progressive renal impairment - untreated, median survival 2 weeks Type 2 – moderate, stable reduction in GFR - median survival 3-6 months Type 2, survival shorter than decomp cirrhotics without renal failure

Hepatorenal Syndrome Treatment Type 1: terlipressin + IV albumin
improvement in Cr in 60-70% reduces short-term mortality Type 2: liver transplantation

Hepatocellular Carcinoma
350,000 deaths annually due to HBV HCC Annual incidence: HBsAg +ve 2.1%/year eAg +ve 3.5%/year eAg seroconversion <30yrs 2.1% >40yrs 7.7% cirrhotics 3-6%/yr, non-cirrhotics %/yr increased risk if family Hx HCC >106cpm 2 3 4 5 6 7 8 9 10 11 12 13 Year of follow-up 5% 10% 15% 1 Cumulative incidence of HCC < 300cpm cpm cpm cpm Yang et al. J Hepatol 2005: 42(suppl 2); 195. 27 27

Prevention: Antivirals Statins? Surveillance and early detection: USS screening AFP Treatment: Resection Ablation Transarterial chemoembolisation (TACE) Liver transplantation

Prevention: Effect of antiviral agents Statins: Some evidence of risk reduction in range of liver diseases, but insufficient for routine use Greater HCC reduction in cirrhotics, older patients, more active disease Effect of HCC reduction mediated by viral suppression Hosaka et al, Hepatology 2013; 58:

Fung J, et al. Hepatology 2005; 42
Hepatocellular Carcinoma: Early Detection Screened vs Non-screened tumours p<0.001 83% p<0.001 64% % of patients p<0.001 46% p<0.001 38% p<0.001 26% 28% 29% 16% 6% 3% Fung J, et al. Hepatology 2005; 42 Gane E (unpublished) Median tumour size: 3cm vs 8cm (p<0.001)

Survival in Hepatocellular Carcinoma Screened vs Non-screened HBV tumours 1 yr 5 yr 10 yr 88% 73% Cumulative Survival Screened group Median survival = 1008 days n = 356 66% Log-rank: P<0.0001 Non-screened group Median survival = 105 days n = 441 10% 27% 9% Survival (Years) Fung J, et al. Hepatology 2005; 42 Gane E (unpublished)

Screening target populations AASLD guidelines: Cirrhotics Asian male >40yrs Asian females >50yrs HBV carrier with FHx HCC NZ: Advanced fibrosis (stage 3 or 4 fibrosis) 6/12ly AFP in other HBsAg +ve patients USS + AFP 6/12ly USS + AFP 6/12ly

Treatments with curative intent Resection: Patients without cirrhosis or cirrhotics without portal hypertension Ablation: Microwave or radio-frequency, percutaneous or open Liver transplant: UCSF criteria – single tumour ≤ 6.5cm OR ≤ 3 tumours, none >4.5cm, cumulative diameter <8cm

Treatments without curative intent Transarterial chemoembolisation (TACE) - purely palliative procedure - delay disease progression in patient on transplant waiting list - bridge to ablation - Only suitable for Child Pugh A or B - Complications: TACE syndrome Liver failure Sorafenib: inhibits tumour cell proliferation and tumour angiogenesis improves median survival ( 7.9mo to 10.9mo) not funded,retail patient charge $14,500/month

Conclusions Effective antiviral therapy has changed the face of hepatitis B - ‘Rescue’ and avoidance of transplantation possible in many decompensated patients Management of decompensation remains important - Whilst awaiting recompensation on antivirals - Patients who do not recompensate on antivirals HCC ongoing challenge in patients with hepatitis B - Antivirals likely to reduce incidence - Early detection key to improving survival in patients with HCC

Managing the Cirrhotic Patient
End Stage Liver Disease and HCC Dominic Ray-Chaudhuri New Zealand Liver Transplant Unit

Disclaimer Please note:
The presentations express the views and opinions of the presenter which are based on the latest information and data available at the time of preparation and are not necessarily endorsed by Gilead Any patient cases and treatment options referred to are in the context of contemporary knowledge and medical practice in the field

Hepatitis B and risk of development of cirrhosis
Lifetime risk of cirrhosis 10-20% Liaw et al, Hepatology 1988;8:

Long-term Lamivudine in Cirrhosis Prevention of Decompensation
651 patients in Australia, NZ and Asia with HBV-cirrhosis received Lamivudine for 3-5 years 21% Placebo (n=215) Cumulative rate of disease progression P<0.001 9% Lamivudine (n=436) Time to disease progression (months) Time (months) Liaw, NEJM,2004 39

Natural History of Cirrhosis
Compensated cirrhosis Asymptomatic, with or without gastric or oesophageal varices Decompensated cirrhosis The development of symptomatic complications of cirrhosis: jaundice, ascites, variceal haemorrhage or hepatic encephalopathy Increased risk of development of hepatocellular carcinoma

Stages of cirrhosis: 5 year outcomes
Compensated Cirrhosis Decompensated cirrhosis D’Amico et al, Aliment Pharmacol Ther 2014;39:

Hepatitis B cirrhosis - prognosis
Hepatitis B sAg +ve cirrhosis: Survival at 1yr 92%, 3yr 79%, 5yr 71% Hepatitis B eAg +ve: 5yr survival 72% eAg –ve: 5yr survival 97% Compensated cirrhosis: 5yr survival 84% Decompensated cirrhosis: 5yr survival 14% De Jongh et al, Gastro 1992; 103: Decompensated = ascites, jaundice, encephalopathy with or without variceal bleeding

Why has decompensation occurred
Treatment naïve patient Viral breakthrough - non-compliance - viral resistance Development of hepatocellular carcinoma Progression due to non-hepatitis B liver disease – alcohol - NASH - co-infection

Management of End Stage Liver Disease
Management of process causing liver damage - treatment of hepatitis B - management of non-hepatitis B liver disease Management of complications - Ascites - Variceal bleeding - Hepatic encephalopathy - Spontaneous bacterial peritontis - Hepatorenal syndrome Consider if possible transplant candidate

Antiviral therapy improves transplant-free survival and liver synthetic function, reduces need for transplant CPT reduced by ≥ 3pts in 61% treated patients, none of controls OLT in 34.8% of treated patients, 73.9% of controls No deaths in treated group, 6 in control group Lamivudine CPT greater than or equal to 10 in all patients Yao et al, Hepatology 2001; 34: