King s College Hospital NHS Foundation Trust Acute Liver Disease: what you really need to know. William Bernal Professor of Liver Critical Care Liver Intensive Therapy Unit Institute of Liver Studies Kings College Hospital United Kingdom NHS Update on Acute Medical and Surgical Emergencies for Psychiatrists Royal College of Psychiatrists 21 st May 2018
Acute Liver Disease: what you really need to know. Liver Intensive Therapy Unit Institute of Liver Studies Kings College Hospital
Acute Liver Disease What you really need to know: Overview. Abnormal Liver Blood tests: What they mean, when to worry & what to do. Hepatic Medical Emergences: Liver Failure Chronic Liver Disease (CLD) Acute Decompensation (AD): what to do? Acute on Chronic Liver failure (ACLF): what is it? Acute Liver Failure (ALF) Recognition and response
Liver Blood Tests Panels vary by laboratory: Hepatobiliary Enzymes Alanine / Aspartate Transaminases (ALT/AST) Alkaline Phosphatase (ALP) Gamma Glutamyl Transferase (GGT) Liver Synthetic Function Tests Bilirubin INR (or Prothrombin Time) Albumin Platelet Count
Liver Blood Tests Hepatobiliary Enzymes Enzyme Site Normal Range ALP AST/ALT Biliary Epithelium (Bone /Placenta) Hepatocytes (Muscle) GGT Hepatocytes / Biliary tract Reflects Elevation 30-130 IU/l Biliary disease Cholestasis Obstruction Infiltration 10-50 IU/l Hepatocyte injury / death 1-55 IU/l Enzyme Induction Cholestasis Hepatitis Hepatic necrosis Congestion Alcohol Steatosis Drugs
Liver Blood Tests Liver Synthetic Function Tests Test Normal Range Reflects Bilirubin 3-20 µmol/l Haem metabolism (Haemolysis) Albumin 35-50 g/l Hepatic synthesis (Loss/Consumption) INR 0.9-1.20 Hepatic Synthesis (Vitamin K Deficiency) Platelets 150-450 x10 9 /l Splenic sequestration Bone marrow suppression Abnormal Gilberts Syndrome Parenchymal Liver disease Biliary Obstruction Parenchymal Liver disease Parenchymal Liver disease Portal Hypertension Alcohol toxicity
Liver Blood Tests Three Common Patterns of Abnormality Pattern Abnormal Tests Causes Clues Isolated Raised Bilirubin Bilirubin Gilberts Syndrome Otherwise Well Haemolysis Anaemia Cholestatic Elevated ALP / GGT Drugs / Alcohol Exposure Obstruction Jaundice Hepatocellular Hepatitic Elevated AST /ALT Liver Cell Injury Hepatic insult
Liver Blood Tests Response to abnormal liver blood tests Newsome et al Gut 2017 6;0:1-14
Liver Blood Tests History Alcohol / Metabolic syndrome & BMI Drug History / Viral risk factors Family history / comorbidity Isolated Raised Bilirubin Otherwise normal LBTs Isolated Cholestatic Liver Enzymes GGT & ALP Hepatitic Liver Enzymes AST / ALT Consider Magnitude Synthetic Failure Jaundice INR Albumin Further Review Concerns: Magnitude Haemolysis Further Review Concerns: Magnitude Absence of obvious cause Weight loss Other abnormal liver tests Urgent Discussion +/ - Urgent Review After Newsome et al Gut 2017 6;0:1-14
Cholestatic Liver Blood Tests 38 year old Female Psychiatric Inpatient Depression No stigmata CLD. Obese (BMI 35), type 2 DM Teetotal Physically well Long term valproate Rx LBT on admission: Blood tests Albumin 39 Bilirubin 17 ALP 112 AST 45 GGT 289 INR 1.1 35-50 g/l 3-20 µmol/l 30-130 IU/L 10-50 IU/L 1-55 IU/L 0.9-1.2 Routine Review Hepatic Steatosis / enzyme induction
Hepatitic Liver Blood Tests 46 year old Male Psychiatric Inpatient Depression No stigmata CLD. Obese (BMI 30) Moderate EtOH Treated hypertension, cholesterol Statin, Amlodopine LBT on admission: Blood tests Albumin 40 Bilirubin 14 ALP 110 AST 150 GGT 46 INR 1.1 35-50 g/l 3-20 µmol/l 30-130 IU/L 10-50 IU/L 1-55 IU/L 0.9-1.2 Routine Review Statin-related Abnormal LBT
Cholestatic Liver Blood Tests 56 year old Male Psychiatric Inpatient Depression No stigmata CLD. Palpable liver edge Thin (BMI 18) Malaise & Weight loss 8 kg. LBT on admission: Blood tests Albumin 29 Bilirubin 60 ALP 450 AST 45 GGT 854 INR 1.6 35-50 g/l 3-20 µmol/l 30-130 IU/L 10-50 IU/L 1-55 IU/L 0.9-1.2 Urgent Review Liver infiltrated by adenocarcinoma
Acute Liver Disease: Liver Failure Two Distinct Clinical Scenarios Decompensated CLD / ACLF Common Pre-existing liver disease: often Cirrhosis Precipitant and decompensation Hepatic failure +/- encephalopathy Acute Liver Failure (ALF) Rare No pre-existing liver disease Acute hepatic insult: commonly Paracetamol Hepatic failure and encephalopathy Cerebral oedema and intracranial hypertension
Chronic Liver Disease
Natural History Chronic Liver Disease. Reduced Hepatic Function Jaundice & Coagulopathy Portal Hypertension Ascites and Variceal Bleeding Porto-systemic shunting/ Liver Failure Hepatic Encephalopathy (HE)
Natural History Chronic Liver Disease. Stable Compensated Cirrhosis (SC) No ascites or overt Hepatic Encephalopathy (HE) ~ 5-10% patients / year Recompensation of hepatic function Acute Decompensated Cirrhosis (AD) Jaundice, Ascites, HE, Variceal bleeding After Bernal et al Lancet 2015;386:1576 1587
Natural History Chronic Liver Disease. D Amico et al J Hepatology 2006;44:217-231
Natural History Chronic Liver Disease Complication 1Year Mortality Variceal Bleeding 20% Ascites 29% Ascites and Variceal Bleeding 49% Hepatic Encephalopathy 64% Jepsen et al Hepatology 2010;51:1675-82. n=466
Natural History Chronic Liver Disease. Stable Compensated Cirrhosis (SC) No ascites or overt HE ~ 5-10% patients / year Recompensation of hepatic function Acute Decompensated Cirrhosis (AD) Jaundice, Ascites, HE, Variceal bleeding ~ 30% hospitalised patients Resolution of organ failures Acute on Chronic Liver Failure (ACLF) Hepatic and Extra-hepatic organ failure? Up to 50% hospitalised patients Death After Bernal et al Lancet 2015;386:1576 1587
Chronic Liver Disease Acute Decompensation Recognise Etiologic clues; Alcohol dependence. Viral Hepatitis. Obesity / diabetes Previously documented Chronic Liver Disease. Previous Decompensation. Physical signs.
Chronic Liver Disease: Signs Compensated Stigmata of CLD Spider nevi Loss of body hair Muscle Wasting Gynaecomastia Palmar Erythema Clubbing Leukonychia Testicular atrophy Decompensated Signs of Decompensation Altered mental state Jaundice Hypotension Bruising Ascites Asterixus GI Bleeding Oedema Markers of Severity
Cholestatic Liver Blood Tests 44 year old Male Psychiatric Outpatient Heavy alcohol use. BMI 22 Not Jaundiced Palmar Erythema. Spider nevae Palpable liver edge LBT on admission: Blood tests Albumin 36 Bilirubin 30 ALP 98 AST 55 GGT 670 INR 1.2 35-50 g/l 3-20 µmol/l 30-130 IU/L 10-50 IU/L 1-55 IU/L 0.9-1.2 Prompt Review Compensated CLD Alcoholic steato-hepatitis
54 year old Male Psychiatric Outpatient Heavy alcohol use. Jaundiced Palmar Erythema. Spider nevae Distended abdomen Swollen ankles LBT on admission: Mixed Liver Blood Tests Blood tests Albumin 30 Bilirubin 110 ALP 70 AST 120 GGT 980 INR 1.7 35-50 g/l 3-20 µmol/l 30-130 IU/L 10-50 IU/L 1-55 IU/L 0.9-1.2 Immediate Review Decompensated CLD Alcoholic Hepatitis
Chronic Liver Disease Precipitants of Acute Decompensation Alcohol-related hepatitis Sepsis Sepsis Drugs (NSAIDs, Opiates, Benzos) Gastro-intestinal bleeding Ischaemic liver injury (sepsis or hypotension) Acute portal vein thrombosis Development of hepatocellular carcinoma
Chronic Liver Disease Acute Decompensation Actions Seek help and prompt bedside review or transfer. Impaired Consciousness / Cardiovascular instability: urgent. Seek / Remove precipitant and initiate Rx. Medication: minimise or discontinue. Benzoidepines / Zopiclone / Opiates Non-steroidals Volume depletion / Electrolyte anomalies: Rehydrate and correct. Renal dysfunction Hyponatraemia Seek / treat sepsis: empiric Rx if concerned. Don t delay
Chronic Liver Disease Early Ward Intervention Cirrhosis and Outcome of Septic Shock: Antibiotic Delay Arabi et al Hepatology 2012 ;56:2305-15 Adjusted OR ; APACHE II, MELD, Immune compromise, Culture +ve
Chronic Liver Disease: AD/ACLF Escalation of care? NCEPOD 2013 Alcohol Related Liver Disease: Measuring the Units Both Advisors and clinicians identified patients in whom escalation of care was not received despite it being indicated....escalation of care should be actively pursued for patients with Alcohol-related Liver disease who deteriorate acutely and whose background functional status is good. There should be close liaison between the medical and critical care teams when making escalation decisions.. www.ncepod.org.uk
ALF the basics: Epidemiology Rare. Younger Adults. High Mortality. Location Era Age Gender Mortality Incidence Spain 1 1992-00 37 56% F 41% 1.4 / million / year Georgia, USA 2 2000-04 38 63% F 47% 5.5 / million / year Scotland 3 1992-09 38 56% F 29% 6.2 / million / year 1 Escorsell et al Liver Transplantation 2007 13:1389-95 2 Bower et al Am J Gastroenterology 2007;102:2459-63 3 Bretherick et al QJM 2011; 104:945-956
ALF the basics: Causes. Aetiology of ALF/ALI Kings College Hospital 1999-2013 n=1204 Paracetamol Non-Paracetamol Bernal et al Unpublished 2018
ALF the basics: Causes. Aetiology of Non-Paracetamol ALF/ALI Kings College Hospital 1999-2013 n=539 Indeterminate DILI Pregnancy-related Viral Ischemia/Hypoxia Malignancy Auto Immune Budd Chiari Wilsons Other Bernal et al Unpublished 2018
ALF: Initial Management Recognise early Circumstantial clues Unexplained confusion / hypoglycaemia Elevated transaminases / coagulopathy Resuscitate Give N-acetyl cysteine (NAC) Give Antibiotics Discuss
ALF: Recognise Early High Risk Paracetamol: Nature & Circumstances of OD Delayed diagnosis Unexplained Agitation / Drowsiness Delayed / Discontinued N-acetyl Cysteine Enhanced hepatotoxicity Coexistent CLD Anorexia / Low BMI HIV
ALF: Recognise Early High Risk Paracetamol Cases Staggered Consumption Delayed Presentation n=611 p<0.01 n=396 p<0.0001 Craig et al Br J Clin Pharmacol 2011 73:2:285-294
ALF: Recognise Early Delayed / Discontinued / Unused N-acetyl Cysteine..A paracetamol concentration either above or just below the line at any time beyond 15 hours of non-staggered ingestion is an indication for treatment with NAC. Postgrad Med J 2005;81:204 216.
ALF: N-acetyl Cysteine (NAC) When to administer? Use the nomogram only as a guide. <8 hrs after ingestion & non-staggered OD Check [paracetamol] and treat if required 8-15 hours Toxic ingestion: start NAC, check [paracetamol] >15 hours after ingestion and non-staggered OD Toxic ingestion: start NAC, check [paracetamol] Staggered OD >150 mg/kg (>75 if high risk) in 24 hrs give NAC If in doubt give NAC and discuss.
ALF: Recognise Early 23 year old Female Psychiatric Inpatient 1 week Depression / DSH No stigmata CLD. Normal LBT on admission Absconded Friday Agitated late Sunday night Hypoglycaemic Blood tests Albumin 36 Bilirubin 38 ALP 112 AST 5476 GGT 25 INR 4.4 35-50 g/l 3-20 µmol/l 30-130 IU/L 10-50 IU/L 1-55 IU/L 0.9-1.2 Immediate Transfer & NAC ALF: Paracetamol
ALF: Recognise Early 28 year old Male Psychiatric Inpatient High risk sexual practices Hospitalised under section 1 month. No stigmata CLD. Normal LBT on admission 12 hours lethargy, withdrawn Hypoglycaemic Blood tests Albumin 30 Bilirubin 180 ALP 96 AST 1876 GGT 150 INR 2.9 35-50 g/l 3-20 µmol/l 30-130 IU/L 10-50 IU/L 1-55 IU/L 0.9-1.2 Immediate Transfer ALF: Acute Hepatitis B
Hospital Survival (%) 90% ALF: Ongoing management. Changing Outcomes Hospital survival in patients with Acute Liver Disease. King s College Hospital 1973 2013. n=3724 80% 70% 60% 50% 40% 30% 20% 10% 0% 1973-78 1979-83 1984-88 1989-93 1994-98 1999-03 2004-08 2009-13 p<0.00001 Bernal Journal of Hepatology. 59 (1):74-80, 2013
Acute Liver Disease: what you really need to know. Identification: History / Examination / Liver Blood Tests. Alarm: Systemic symptoms & Signs / Synthetic dysfunction. Chronic Liver Disease >> Acute Liver Failure Chronic Liver Disease Signs / Laboratory tests of decompensation. Urgent transfer / fluids / antibiotics. Acute Liver Failure Early recognition. Liver Blood tests: Hepatic Necrosis / Synthetic Failure. Most commonly Paracetmol: NAC and urgent transfer.