Week 6 - A - Acute & fulminant liver failure (causes, treatment), hepatic encephalopathy (features/treatment), paracetamol

Question 1

What is the dual blood supply to the liver? What is the drainage of the liver?

Answer 1

O2 rich blood flows into the liver through hepatic artery Nutrient rich blood coming from the bowel flows into the liver through the hepatic portal vein Bile flows out of the liver through R+L hepatic duct into common hepatic duct Blood flows out of the liver through 3 hepatic veins which drain into IVC

Question 2

What are the different functions of the liver?

Answer 2

* Protein metabolism * Carbohydrate metabolism * Lipid metabolism * Bile acid metabolism * Bilirubin metabolism * Hormone and drug metabolism * Produce coagulation factors * Immunological defence

Question 3

The liver is very resistant to injury and has a large functional reserve * Some insults can cause severe parenchymal necrosis but heal entirely * Some insults can leave permanent damage * Some insults produce predictable pathological patterns * What is acute liver failure defined as?

Answer 3

Acute liver failure is defined as the rapid development of hepatic dysfunction in patients with no prior evidence of liver disease - less than 6 months duration

Question 4

What is acute liver failure characterised by?

Answer 4

Acute liver failure is characterised by * Jaundice * Coagulopathy - INR >1.5 * Encephalopathy

Question 5

What are the different causes of acute liver disease?

Answer 5

paracetamol overdose alcohol viral hepatitis (usually A or B) (can be caused by hepatitis E) Bile duct obstruction acute fatty liver of pregnancy Chronic liver disease

Question 6

What are the clinical features of acute liver disease?

Answer 6

* Jaundice * Lethargy * Nausea * Anorexia * Hepatic encephalopathy * Pain * Itch * Arthralgia

Question 7

SHORT BIT ON ECEPHALOPATHY What is the proposed pathogenesis of encephalopathy? * Why is there excess ammonia? * What tries to clear this ammonia once in the brain? * What does this cause a build up of?

Answer 7

IT IS THE BUILD UP OF AMMONIA THAT CAUSES THE FEATURES OF ENCEPHALOPATHY * As the liver fails, nitrogenous waste (as ammonia) from bacterial breakdown of proteins in the gut builds up in the circulation * The ammonia then passes to the brain * The astrocytes in the brain clear the ammonia by a process involving the conversion of glutamate to glutamine * The excess glutamine causes different features

Question 8

What does the excess glutamine build up in the brain cause to the brain cells?

Answer 8

The excess glutamine causes an osmotic imabalance and a shift of fluid into the astrocytes which become swollen leading to cerebral oedema The excess glutamine also causes oxdative stress to the cells of the brain This leads to certain clinical features of encephalopathy

Question 9

What are the 4 main domains of the manifestation of hepatic encephalopathy? (as severity of the encephalopathy increases, the changes in each of the domains will worsen)

Answer 9

Level of consciousness / alertness Intellectual function - confusion Neuromuscular abnormalities Personalitiy and behaviour

Question 10

Two findings common in hepatic encephalopathy are asterixis and apraxia/dyspraxia * What is asterixis? - what happens here?

Answer 10

Asterixis is a classical finding - intermittent, abrupt and brief loss of muscle tone (aka negative myoclonus) - seen when patients outstretch their arms and you witness their hand flapping - aka liver flap

Question 11

What is dyspraxia / apraxia? What can you ask the patient to carry out to demonstrate this feature?

Answer 11

Dyspraxia / apraxia is the partial / complete loss of the ability to co-ordinate and perform skilled, purposeful movements and gestures with normal accuracy Can ask the patient to copy a 5 point star and they prove incapable of doing so

Question 12

Hepatic encephalopathy features can be graded from I to IV depending on the severity What falls under each grade?

Answer 12

Grade I Irritable, reversed sleep pattern, mild confusion, dyspraxia Grade II Increasing drowsiness and confusion, liver flap may be present, inapropriate behaviour Grade III Incoherent, restless, liver flap, ataxia, stupor Grade IV - coma

Question 13

How is hepatic encephalopathy diagnosed?

Answer 13

There is no diagnostic test - usually a clinical diagnosis with possibly measuring ammonia levels - not routinely done any more

Question 14

In the management of hepatic encephalopathy, what is given first line? What is added for the secondary prevention of hepatic encephalopathy?

Answer 14

Lactulose is recommended first line by NICE - lactulose is thought to work by promoting the excretion of ammonia and increasing the metabolism of ammonia by gut bacteria Rifaximin (the antibiotic given in small bowel bacterial overgrowth syndrome) is added second line to prevent future hepatic encephalopathy - it is thought to decrease urease forming bacteria reducing ammonia production

Question 15

BACK TO ACUTE LIVER FAILURE History is definitely the most important way of determining acute liver failure What investigations are carried out in assessing acute liver failure?

Answer 15

LFTs Prothrombin time (INR) Virology - if suspecting viral cause Paracetemol level if suspecting drug overdose Investigations of chronic level disease eg storage diseases

Question 16

What is seen on the liver function tests in acute liver failure? What happens to the albumin level in acute liver failure?

Answer 16

* INR > 1.5 (raised prothrombin time) * Hyperbilrubinaemia * Raised ALT (alanine transaminase) and AST (aspartate transaminae) Decreased serum albumin levels are not seen in acute liver failure because it takes several weeks of impaired albumin production before the serum albumin level drops. The most common reason for a low albumin is chronic liver failure caused by cirrhosis.

Question 17

What is the management of acute liver failure? Beware of * Sepsis * Hypoglycaemia * GI bleeds/varices * Encephalopathy

Answer 17

Intensive care monitoring is mandatory once hepatic encephalopathy is present - tracheal intubation and NG tube to protect airway and avoid aspiration Give IV glucose to avoid hypo Treat the underlying cause * Try to avoid sedatives and other drugs with hepatic metabolism * Monitor blood glucose, electrolytes and cultures

Question 18

Which drugs are hepatotxic and therefore should be avoided in liver failure?

Answer 18

Avoid * Paracetamol * Methotrexate * Isioniazid * Tetracyclines * Salicyates

Question 19

What are the different outcomes of acute liver failure?

Answer 19

• complete recovery - chronic liver disease - death from liver failure

Question 20

What is fulminant hepatic failure?

Answer 20

Fulminant hepatic failure is an acute episode of severe liver dysfunction (jaundice and encephalopathy) due to massive necrosis of liver cells in a patient with previous normal liver (essentially it is just a very severe acute liver failure)

Question 21

What are the different features of fulminant hepatic failure?

Answer 21

* Encephalopathy * Hypoglycaemia * Coagulopathy * Circulatory failure * Renal failure * Infection

Question 22

Treatment of fulminant liver failure are the same as acute liver failure Intensive care monitoring is mandatory once hepatic encephalopathy is present - tracheal intubation and NG tube to protect airway and avoid aspiration Give IV glucose to avoid hypo Treat the underlying cause Treat arising complications What are some complications of acute/fulminant liver failure?

Answer 22

Cerebral oedema Ascites Bleeding Infection Hypoglycaemia Encephalopathy

Question 23

How are each of the complications treated? Cerebral oedema Ascites Bleeding Infection Hypoglycaemia Encephalopathy

Answer 23

Cerebral oedema - give mannitol IV Ascites - restrict fluid, low-slat diet and diuretics Bleeding - vitamin K, FFP + Major haemorrhage protocol if needed +/- endoscopy if due to oeseophageal varices Infection - empircal therapy Hypoglycaemia - IV glucose Encephalopathy - give lactulose, rifaximin added to prevent future occurence

Question 24

In fulminant hepatic failure What is always important to consider?

Answer 24

It is important to consider the potential need for a liver transplant - will require life-long immunosuppresion

Question 25

Some different causes of acute liver failure * Paracetamol * alcohol * viral hepatitis (usually A or B) (can be caused by E) * Bile duct obstruction * acute fatty liver of pregnancy * Acute on Chronic liver disease Lets discuss paracetamol * Which patients are at an increased risk of hepatoxicity following a paracetamol overdose?

Answer 25

The following groups of patients are at an increased risk of developing hepatotoxicity following a paracetamol overdose: patients taking liver enzyme-inducing drugs (rifampicin, phenytoin, carbamazepine, chronic alcohol excess, St John’s Wort) malnourished patients (e.g. anorexia nervosa) or patients who have not eaten for a few days

Question 26

What is a paracetamol overdose? Below which dose in 24 hours is toxicity unlikely?

Answer 26

The recommended dose of paracetamol is 4 g (or 75 mg/kg) in 24 hours for an adult patient. Any ingestion exceeding this is regarded as an overdose. Toxicity is extremely unlikely if the patient has consumed less than 75mg/kg within 24 hours

Question 27

What is the difference between a * simple acute paracetamol overdose * a staggered paracetamol overdose * unintentional therapeutic overdose

Answer 27

* Single acute overdose is defined as an ingestion of >4 g (or >75 mg/kg) in a period of 1 hour (usually with the intention of self-harm) * Unintentional therapeutic overdose denotes ingestion of excess paracetamol with intent to treat pain or fever (i.e., without self-harm intent)

Question 28

How is paracetamol normally metabolised within the body? * What metabolises about 90% of paracetamol? * What is the toxic intermediate compound from the cytochome P450 breakdown pathway? * What breaks this intermediate metabolite down in normal circumstances?

Answer 28

In normal conditions, paracetamol is mostly converted to nontoxic metabolites by conjugation with sulfate and glucuronide * A small percentage is oxidised by CP450 enzyme to system to the highly reactive intermediate metabolite N-acetyl-p-benzoquinone imine (NAPQI) * Under normal conditions, NAPQI is detoxified by conjugation with glutathione to form cysteine and mercapturic acid conjugates

Question 29

Image showing how normally paracetamol is conjugated with sulfate/glucoronide or goes through cP450 and then metabolised by glutathionine to non toxic conjugates What happens in paracetamol overdose? How does this cause hepatoxicity?

Answer 29

In cases of paracetamol overdose, the sulfate and glucuronide pathways become saturated, and more paracetamol is shunted to the cytochrome P450 system to produce NAPQI (N-acetyl-p-benzoquinoneimine) * As a result, hepatocellular supplies of glutathione become depleted, as the demand for glutathione is higher than its regeneration. * NAPQI therefore remains in its toxic form in the liver and reacts with cellular membrane molecules, resulting in widespread hepatocyte damage and death, leading to acute liver necrosis

Question 30

Why is paracetamol levels not measured in the first 4 hours following a paracetamol overdose?

Answer 30

A paracetamol level drawn in the first four hours after ingestion may underestimate the amount in the system because paracetamol may still be in the process of being absorbed from the gastrointestinal tract. Therefore, a serum level taken before 4 hours is not recommended

Question 31

What are the presenting features of a paracetamol overdose? What investigations are carried out?

Answer 31

Presenting features Vomiting + RUQ pain initially Later - jaundice and encephalopathy from the liver damage Investigations * Measure blood paracetamol levels at 4 hours * LFTs - ALT/AST and biluribin all raised, raised prothrombin time

Question 32

What can be given to patients presenting within one hour of paracetamol ingestion and how does it work? * What is the main treatment of choice in paracetamol ingestion? how does it work? * If given in what time frame can it prevent hepatotoxicity?

Answer 32

Within one hour of presentation, oral activated charcoal can be given to the patient - the charcoal binds to the poison and prevents further absorption into the blood. Main treatment of choice in patients is IV N-acetylcysteine - aka Acetylcysteine/NAC, works to reduce paracetamol toxicity by replenishing body stores of the antioxidant glutathione * If given within 8 hours, it can prevent hepatotoxicity

Question 33

What are the indications for giving N-acetylcysteine in a paracetamol overdose?

Answer 33

Give N-acetylcysteine in patients whom

• * There is a staggered overdose or there is doubt over the time of paracetamol ingestion, regardless of the plasma paracetamol concentration
• Those who ingested all tablets within one hour:
  
  • * Plasma-paracetamol conc falls on or above the treatment line on the paracetamol normogram;
  • * Who present 8–24 hours after taking an acute overdose of more than 150 mg/kg of paracetamol, even if plasma-paracetamol conc is not yet available

Question 34

The King’s College Criteria or the King’s College Hospital criteria were devised in 1989 to determine if there were any early indices of poor prognosis in patients with acute liver failure.

The criteria separates paracetamol induced vs non paracetamol induced acute liver failure for prioritising liver transplant in these patients

What are the different criteria for paracetamol and non paracetamol induced acute liver failure indicating a need for probabaly liver transplant?

Answer 34