Acute Liver Failure ACCS ST 1 Alain Sauvage

Acute Liver Failure ACCS ST 1 Alain Sauvage

Topics l l Definitions of failure and classification Aetiology- Acute versus acute on chronic Basic diagnostic workup Treatment of complication l l Hepatic encephalopathy Coagulopathy Specialist centre referral Organ support

The mortality rate for acute liver failure ranges between 56% and 80%

l UK incidence of cirrhosis 17 per 100, 000 l Prevalence of cirrhosis is 76 per 100, 000 l ALF incidence is 1 -6 per million per year

Formal diagnosis of acute liver failure l An increase in PT by 4 -6 seconds (INR>1. 5) l And the development of hepatic encephalopathy (HE). l In a patient without pre-existing cirrhosis and with an illness of less than six months duration.

Definition; Jaundice to HE l Hyperacutel Acute - >7 days <21 days l Subacutel FHF- <7 days >21 days <6 months not used

Stages of Hepatic Encephalopathy: Stage 0. Lack of detectable changes in personality or behaviour. Asterixis absent. Stage 1. Trivial lack of awareness. Shortened attention span. Impaired addition or subtraction. Hypersomnia, insomnia, or inversion of sleep pattern. Euphoria or depression. Asterixis can be detected. Stage 2. Lethargy or apathy. Disorientation. Inappropriate behaviour. Slurred speech. Obvious asterixis. Stage 3. Gross disorientation. Bizarre behaviour. Semistupor to stupor. Asterixis generally absent. Stage 4. Coma.

Worldwide cause varies

Diagnostics: l Good history- difficult if HE

Diagnosis and Initial Evaluation ALF § § § § HISTORY: Family members with liver disease? Recent cold sores Onset of jaundice Work environment- toxic agents Hobbies/travel Herbal products/dietary supplements

Initial Laboratory Analysis l l l Prothrombin time/INR Chemistries Liver enzymes Arterial blood gas Paracetamol level, Toxicology screen Viral hepatitis serologies (anti-HAV Ig. M, HBs. Ag, anti-HBc Ig. M, anti-HEV, anti-HCV, HCV RNA , HSV 1 Ig. M, VZ/HS, EB, CMV)

Initial Laboratory Analysis l Ceruloplasmin level l Pregnancy test (females) l Ammonia (arterial if possible) l Autoimmune Markers (ANA, ASMA, Immunoglobulin levels )

Liver biopsy for diagnostic dilemma l Importance of early biopsy- severity and aetiology l Particularly useful in Hep B, Autoimmune, Alcoholic hepatitis, differentiate between ALF and ACLF l Transjugular route

What are the potential outcomes? l Recovery because of a successful intervention l l NAC for paracetamol toxicity Antivirals for acute hepatitis B l Spontaneous recovery with supportive care l Death l Rescue by liver transplant (OLT)

Aetiology outcome for ALF Transplant free survival >50% l Hepatitis A, FLDP, paracetamol Transplant free survival <25% l Autoimmune, HEB, Wilsons, mushroom, idiosyncratic drug

All Liver transplants l CLD – 60% l Malignancy- 10% l ALF- 10% ( Paracetamol) l Cholestasis - 10 -20%

King’s College Criteria LT l Acetaminophen-Induced ALF: l l Strongly consider OLT listing if: arterial lactate >3. 5 mmol/L after early fluid resuscitation List for OLT if: p. H<7. 3 Or arterial lactate >3. 0 mmol/L after adequate fluid resuscitation List for OLT if all 3 occur within a 24 -hour period: 1 - presence of grade 3 or 4 hepatic encephalopathy 2 - INR >6. 5 3 - Creatinine >3. 4 mg/d. L l l l

King’s College Criteria LT l Non-acetaminophen: l INR > 6. 5 OR l Any 3 of the following 5: l l l Age < 10 or > 40 Serum bilirubin > 300 Jaundice to encephalopathy interval > 7 days INR > 3. 5 Unfavorable Etiology l Non-A, non-B hepatitis, halothane, idiosyncratic drug reaction, Wilson’s

Case 1 l 21 yo presents with N&V l Found to be tender at RUQ l History of paracetamol OD 24 g 3/7 ago l ALT 2, 200, PT 22 sec, albumin 30 What next?

Paracetamol Overdose Stage I – 0 -24 h l Asymptomatic l GI upset l LFT derangement at 12 h l Stage 2 – 24 -48 h l RUQ pain, tenderness l LFT derrangment, bilirubin, PT l Stage 3 – 48 -96 h l Centrilobar necrosis l Liver failure l Stage 4 l Recovery, transplant or death l No chronic state l

When to pick up the phone l D 2 l l l D 3 l l p. H <7. 3 INR>3 Cr >200 Hypoglycaemia HE Cr>200 INR >4. 5 D 4 l l l Any rise in INR Cr >250 HE

l Following phone call, transferred to a liver specialist intensive care

Encephalopathy

HE- Four compatible theories l Cerebral vasomotor dysfunction l Oedema secondary to ammonia toxicity l Inflammation due to SIRS l putative benzodiazepine-like molecules

The pathophysiology of HE l Ammonia as a key factor in the pathogenesis of HE. l Portal ammonia is derived from both the l l urease activity of colonic bacteria and the de-amidation of glutamine in the small bowel. The intact liver clears almost all of the portal vein ammonia, converting it into glutamine and preventing entry into the systemic circulation. l Ammonia- astrocyte swelling in brain l

Cerebral Edema l Degree of encephalopathy correlates w/ cerebral edema Grade I-II: rare l Grade III: 25 -35% risk l Grade IV: 65 -75% risk l l Uncal herniation l Compromises cerebral blood flow hypoxic brain injury

Grade III/IV Encephalopathy Intubate trachea + ventilate Elevate head of bed Consider placement of ICP monitoring device Immediate treatment of seizures required; prophylaxis of unclear value l Mannitol: use for severe elevation of ICP or first clinical signs of herniation l Hypertonic saline to raise serum sodium to 145155 mmol/L l Hyperventilation: effects short-lived; may use for impending herniation l l

GCS –HE correlation l Grade 1 - GCS 14 -15 l Grade 2 - GCS 11 -13 - HDU l Grade 3 - GCS 8 -11 (Stupor or precoma) l Grade 4 - GCS<8 (Coma)

Lactulose is a first-line pharmacological treatment of HE. Lactulose – reaches colon, where bacteria will metabolize the lactulose to acetic acid and lactic acid. l This lowers the colonic p. H l formation of the non-absorbable NH 4+ from NH 3, l Other effects like catharsis also contribute to the clinical effectiveness of lactulose. l

Lactulose l For acute encephalopathy, lactulose (ingested or via nasogastric tube), 45 ml p. o. , Is followed by dosing every hour until evacuation occurs. l Target -three soft bowel movements per day l l If response to disachharide is poor- add antibiotic (metronidazole or rifaximine after 48 Hrs) to reduce enteric bacterial mass.

The coagulopathy of liver disease l Failure to produce clotting factors II, V, VII and IX l l The degree of coagulopathy is a measure of severity of liver disease and of patient prognosis. Routine correction of coaguloapthy is therefore NOT indicated unless active bleeding or planned interventions require it l l Vitamin K: give at least one dose FFP: give only for invasive procedures or active bleeding Platelets: give only for invasive procedures or active bleeding Recombinant activated factor VII: possibly effective for invasive procedures

Role of prophylactic antibiotic l Only patients who have an episode of gastrointestinal bleeding l or an episode of spontaneous bacterial peritonitis (SBP) have been shown to have a significant outcome benefit from prophylactic antibiotics.

Role of NAC Efficacy of NAC is well established in paracetamol induced ALF l Non PCM ALF – role of NAC is controversial l However most recent studies has improved outcome 175 patients of non PCM ALF received NAC l l Transplant free survival at 3 weeks was 52% in NAC group compared to 30% in placebo arm ( only with coma grade of 1 -2) United States ALF study group- overall was 70% vs 66%

Artificial liver? ?

Extracorporeal Liver Assist Device (ELAD) l Hepatocyte bioreactor- hepatoma cells cultivated on the exterior surface of semipermeable hollow fibres l MARS (molecular adsorbent recirculating system)

ELAD l Both reduce the level of bilirubin, bile salt ammonia etc l However no of patients dying or requiring liver transplant did not improve Devices remain experimental and large-scale phase two and three trials are awaited

Case 2 l 55 yo Male, builder bricklayer l PMH Alcohol abuse (abstinent) l Recurrent ascites l Oesophageal varices l l Meds l Thiamine, vit B 12, furosemide/amiloride, lactulose, propranolol

Case 2 l PC l Tired, fatigued, reversal of sleep wake pattern, generalized slowness, l Exam l Spider naevi, no asterixis, splenomegally, mild shifting dullness, INR 1. 3, plt 115, Hb 14. 5, MCV 101, alb 48, ALP 110, ALT 32 l What next ? . . .

Stages of Hepatic Encephalopathy: Stage 0. Lack of detectable changes in personality or behaviour. Asterixis absent. Stage 1. Trivial lack of awareness. Shortened attention span. Impaired addition or subtraction. Hypersomnia, insomnia, or inversion of sleep pattern. Euphoria or depression. Asterixis can be detected. Stage 2. Lethargy or apathy. Disorientation. Inappropriate behaviour. Slurred speech. Obvious asterixis. Stage 3. Gross disorientation. Bizarre behaviour. Semistupor to stupor. Asterixis generally absent. Stage 4. Coma.

Acute on Chronic Liver Failure ACLF l This entity is quite common- background of cirrhosis. Innocent precipitating event culminates in Massive Organ Failure (OF) l Events Toxins (alcohol!) l Vascular (hypotension- GI bleed, dehydration, Portal vein thrombosis) l Infection (SBP) l

For patients with ACLF l Young age l First presentation l Reversible pathology- sepsis, GI bleeding or severe hepatitis l A trip to ITU is a life changing experience to some ‘alcoholics’

Summary • The mortality rate for acute liver failure ranges between 56% and 80% • Careful history taking and examination of lab results help identify patients • The commonest cause of acute liver failure in the western world is paracetamol toxicity l Some causes have low survival without OLT, prompt referral… • Hepatic encephalopathy is no longer the main cause of death but it’s detection and management requires sophisticated cardiovascular and cerebral monitoring • Acute on Chronic Liver Failure

Reference ALF l FS Cardoso, P Marcelino, L Bagulho. Acute liver failure: An up to date approach; Jn critical care 39(2017)25 -30

Reference Acute Fatty Liver of Pregnancy l l Ronen, Shahzeb, Steinberg. Acute Fatty Liver of Pregnancy: A Thorough Examination of a Harmful Obstetrical Syndrome and Its Counterparts. https: //www. ncbi. nlm. nih. gov/pmc/articles/PMC 5889153/ Dyna. Med Plus www. dynamed. com (check with your library if your hospital has an account, it is a less flashy/organised version of uptodate)