Hepatology on the AMU - PDF Free Download

Hepatology on the AMU RCP day, 8 th February 2018 Jo Leithead Consultant in Hepatology and Liver Transplantation Addenbrookes Hospital Cambridge

Is liver disease relevant to me? Williams R, Lancet 2014

Is liver disease relevant to me? Leon DA, Lancet 2006

Is liver disease relevant to me? Number (prop) At risk of liver disease 12,000,000 (1/5) Basis of estimate With significant liver disease 600,000 (1/100) Estimated from end-stage figures/natural history With cirrhosis 60,000 (1/1000) Estimated from sources/natural history Have primary liver cancer Have liver disease as direct cause of death 3000/yr(1/20,000) Undergo liver transplantation 800 (1/70,000) 12,000 (1/5,000) Contributoryin 36,000 deaths/anum Liver Disease: The NHS Atlas of Variation in Healthcare for People with Liver Disease

I want us to be up there with the best in Europe when it comes to tackling the leading causes of early death, starting with the five big killer diseases cancer, heart, stroke, respiratory and liver disease.

NCEPOD review (2013) Consultant Hepatologistspresent in only 28% of hospitals ( with an interest in 73% DGHs and 81% teaching hospitals) 1/3 of patients who were thought to have required escalation of care did not receive it due to reluctance to escalate in ARLD A decision to limit care/withdraw treatment was inappropriate in 17% In more thant 1/2 overall care was rated as having room for improvement /poor

The postcode lottery Williams R, Lancet 2014

The postcode lottery Social deprivation late presentation and comorbidity Education of primary care late diagnosis Imbalance in transplant centres - education and access to e.g. TIPSS/transfer Williams R, Lancet 2014

Aims What is acute on chronic liver disease? Pathophysiology Specific aspects to get you through the weekend! circulatory and renal dysfunction, nutrition Who to escalate to ITU? Role of transplant

What is acute on chronic liver disease?

Spectrum of chronic liver disease STEATOSIS e.g. alcoholic liver disease, nonalcoholic fatty liver disease HEPATOCELLULAR CARCINOMA INFLAMMATION e.g. viral, autoimmune, alcohol, wilson s, drugs FIBROSIS CIRRHOSIS MALNUTRITION IRON OVERLOAD e.g. hereditoryhaemochromatosis, secondary iron overload NON-CIRRHOTIC: Pre-hepatic e.g. portal vein thrombosis Intra-hepatic e.g noncirrhotic portal hypertension, schistosomiasis Post-hepatic e.g. Buddchiarisyndrome, cardiac failure PORTAL HYPERTENSION VARICES ASCITES RENAL DYSFUNCTION ENCEPHALOPATHY ASYMPTOMATIC SYMPTOMATIC

What is acute on chronic liver disease? Characteristicsof patientsadmitted with acute decompensation (n=1343) Mean age (yrs) 57.2 Male sex (%) 64 Aetiology of cirrhosis (%): Alcohol Hepatitis C Alcohol plus hepatitis C Any previous hospitalisation (%) 47 Cause of current hospitalisation (%) Ascites Encephalopathy GI haemorrhage Bacterial infection 52 20 10 67 34 16 24 Moreau R (CANIONIC study), Gastroenterology 2013

What is acute on chronic liver disease? Decompensated cirrhosis = hepatic and other organ dysfunction occurring in the context of gradual progression of cirrhosis over months. Bernal W, Lancet 2015

What is acute on chronic liver disease? Decompensated cirrhosis = hepatic and other organ dysfunction occurring in the context of gradual progression of cirrhosis over months. Acute on chronic liver failure = Short-term deterioration in hepatic and other organ function in a patient with chronic liver disease over days to several weeks after a defined or undefined precipitating illness Bernal W, Lancet 2015

Jalan R, J Hepatology 2012

Acute alcoholic hepatitis Typically will have stopped drinking 1-2 weeks before presentation Severe hepatic inflammation often leading to SIRS and multiorgan dysfunction Hotchkiss RS, Nat Med 2009

Acute alcoholic hepatitis Typically will have stopped drinking 1-2 weeks before presentation Severe hepatic inflammation often leading to SIRS and multiorgan dysfunction Labs PT Increased Bilirubin 250-1000 ALT ~100-200 Alk phos ~150-300 Albumin Low WCC O en CRP <50 Forrest E, Gut 2005

Pathophysiology

The baseline multiorgan dysfunction

Portal hypertension Splanchnic vasodilatation with reduced effective circulating volume Leithead/Hayes/Ferguson, AP&T 2014

Portal hypertension Splanchnic vasodilatation with reduced effective circulating volume Increased SNS, RAAS, vaspressin Leithead/Hayes/Ferguson, AP&T 2014

Portal hypertension Splanchnic vasodilatation with reduced effective circulating volume Increased cardiac output Increased SNS, RAAS, vaspressin Leithead/Hayes/Ferguson, AP&T 2014

Portal hypertension Splanchnic vasodilatation with reduced effective circulating volume Cardiac dysfunction Increased SNS, RAAS, vaspressin Leithead/Hayes/Ferguson, AP&T 2014

Portal hypertension Bacterial translocation with low grade SIRS Splanchnic vasodilatation with reduced effective circulating volume Cardiac dysfunction Increased SNS, RAAS, vaspressin Leithead/Hayes/Ferguson, AP&T 2014

DIURETICS LVP Portal hypertension Bacterial translocation with low grade SIRS? Hepato-renal reflex Splanchnic vasodilatation with reduced effective circulating volume Cardiac dysfunction Increased SNS, RAAS, vaspressin Leithead/Hayes/Ferguson, AP&T 2014

DIURETICS LVP INFECTION HAEMORRHAGE Portal hypertension Bacterial translocation with low grade SIRS? Hepato-renal reflex Splanchnic vasodilatation with reduced effective circulating volume Cardiac dysfunction Increased SNS, RAAS, vaspressin Leithead/Hayes/Ferguson, AP&T 2014

DIURETICS LVP INFECTION HAEMORRHAGE SIRS? Hepato-renal reflex Portal hypertension Bacterial translocation with low grade SIRS Splanchnic vasodilatation with reduced effective circulating volume Cardiac dysfunction Increased SNS, RAAS, vaspressin Leithead/Hayes/Ferguson, AP&T 2014

Portal hypertension Bacterial translocation with low grade SIRS? Hepato-renal reflex Splanchnic vasodilatation with reduced effective circulating volume Cardiac dysfunction Increased SNS, RAAS, vaspressin Leithead/Hayes/Ferguson, AP&T 2014

The baseline multiorgan dysfunction Portal hypertension Bacterial translocation with low grade SIRS SPLANCHNIC VASODILATATION WITH REDUCED EFFECTIVE CIRCULATING VOLUME Cardiac dysfunction Increased SNS, RAAS, vaspressin Leithead/Hayes/Ferguson, AP&T 2014

Portal hypertension related renal dysfunction Diuretic controlled ascites Hyponatraemia Refractory ascites Hepatorenal syndrome Leithead/Hayes/Ferguson, AP&T 2014

Specific aspects to get you through the weekend

The basics Treat the cause low threshold for antibiotics, consider invasive fungal infection Prevent circulatory and renal dysfunction Rifaximin, lactulose, enemas Stop NSAIDS, ACE inhibtors, other nephrotoxics; avoid sedating medication Nutrition

Managing the circulatory and renal dysfunction

Managing the circulatory and renal dysfunction TOP TIPS Ascites is your marker of renal dysfunction Creatinine is falsely low Aim is to increase the effective circulating volume to reduce endogenous vasoactive mediators.

Managing the circulatory and renal dysfunction Vasoconstrictors - Terlipressin Reverses type 1 HRS and on meta-analysis results in a small reduction in short-term mortality. But 13% 6-month transplant free survival. Noradrenaline as effective Intravenous human albumin Volume loads plus increases oncotic pressure, binds endotoxin, and has antiinflammatory and antioxidant effect; may impact on endothelial and cardiac dysfunction. Garcia-Martinez et al, Hepatology 2013 Fernandez et al, J Hepatol 2005 Fernandez et al, Hepatology 2005 Ortega et al, Hepatology 2002 Gluud et al, Cochrane Database Syst Rev 2012 Sanyal et al, Gastroenterology 2008 Salerno et al, Gut 2007 Alessandria et al, J Hepatol 2007 Sharma et al, Am J Gastroenterol 2008 Singh et al, J Hepatol2012

Managing the circulatory and renal dysfunction Vasoconstrictors - Terlipressin Reverses type 1 HRS and on meta-analysis results in a small reduction in short-term mortality. But 13% 6-month transplant free survival. Noradrenaline as effective Intravenous human albumin Volume loads plus increases oncotic pressure, binds endotoxin, and has antiinflammatory and antioxidant effect; may impact on endothelial and cardiac dysfunction. In HRS, results in a 3x increased rate of reversal of renal dysfunction compared to terlipressin alone. Garcia-Martinez et al, Hepatology 2013 Fernandez et al, J Hepatol 2005 Fernandez et al, Hepatology 2005 Ortega et al, Hepatology 2002 Gluud et al, Cochrane Database Syst Rev 2012 Sanyal et al, Gastroenterology 2008 Salerno et al, Gut 2007 Alessandria et al, J Hepatol 2007 Sharma et al, Am J Gastroenterol 2008 Singh et al, J Hepatol2012

Managing the circulatory and renal dysfunction Key points re fluid filling The fluid is in the wrong place Leaky pulmonary circulation CVP not helpful Avoid 5% dextrose (<5% remains intravascular) 500ml 5% = 100 mls20% = 20g albumin 40-60g albumin/24 hours (serum albumin does not dictate amount to give)

Managing the circulatory and renal dysfunction Key points re ascites Only drain if causing problems ventilating/patient distress (but all patients should have a diagnostic tap) Renal dysfunction is not a contraindication to large volume paracentesis 20g albumin for every 2-3L drained Remove drain within 6-12 hours

Paracentesis Umgelteret al, CritCare 2008

Nutrition

Nutrition Malnutrition and sarcopenia The norm in advanced liver disease including overweight patients Multi-factorial Catabolic state Anorexia (jaundice, ascites) Malabsorption of fat and fat-soluble vitamins Protein loss (ascites, protein loosing enteropathy, nephrotic syndrome) Nutrition intricately linked with immune function therefore increased risk of infection. Increasingly recognised as a poor prognostic indicator

Nutrition Cirrhotic eating pattern: carbohydrate consumption every 2-3 hours (little and often eating pattern) and 50g bedtime carbohydrate snack prevents gluconeogenesis High protein intake recommended (1.2-1.5g/kg) Do not protein restrict no evidence this improves HE and may actually worsen it by causing muscle catabolism. Muscle plays important role in ammonia removal in liver disease High energy, high protein low volume oral nutritional supplement drinks useful Low threshold for enteral nutrition support if oral intake not meeting requirements Dietitianreferral for monitoring of nutritional status (MUAC, MAMC, HGS) and specialist advice If at risk of refeedingsyndrome: refeedingvitamins, gradual introduction of nutrition (but not too slow) and monitor K, Mg, PO4 and AdjCa

What s needed to meet requirements? 70kg Man: 2600kcal, 84-105g protein/day Breakfast Supper Snacks 400kcal 12.5g protein Lunch 370kcal 14g protein Total 2645kcal Bedtime 96.5g 310kcal 13g protein Supplements 680kcal 25g protein 285kcal 8g protein 600kcal 24g protein

Who to escalate to ITU?

Birmingham liver transplant waiting list survival

Jalan R, J Hepatology 2012

Bernal W, Lancet 2015

Cholangitas, AP&T 2006

GinesP, J Hepatol2012

CLIF-SOFA score Organ failure Liver Bilirubin>200 Kidney Creatinine>177 Cerebral Encephalopathy grade III/IV Coag INR 2.5/platelets<20 Circ Any vasopressor (incl terli) Lungs Pa02/Fi02 200 Moreau R, J Hepatology 2012

Mechanical ventilation (45%) 26 Vasopressors (41%) 19 RRT (10%) 10 0 20 40 60 80 100 % survival Severe infection 36 Type 1 HRS 58 Hepatic encephalopathy 74 Variceal haemorrhage 77 0 20 40 60 80 100 % survival Levesque E, J Hepatology 2012

Das V, CritCare Med 2010

Role of transplantation.

Final comments Patients frequently present late and prognosis may be short Often socially isolated/vulnerable End of life care

Questions