Acute Liver Failure

Question 1

Define acute liver failure

Answer 1

Acute liver failure is a syndrome of acute liver dysfunction without underlying chronic liver disease.

Question 2

ALF is an … condition associated with a … mortality.

Answer 2

ALF is an uncommon condition associated with a high mortality.

Question 3

ALF is characterised by … (… in …) of hepatic origin and altered levels of consciousness due to hepatic …. (HE).

Answer 3

ALF is characterised by coagulopathy (derangement in clotting) of hepatic origin and altered levels of consciousness due to hepatic encephalopathy (HE).

Question 4

The cause of ALF is numerous, but drug-induced liver injury (DILI) is the most common reason in Europe. This may be divided into … or non-… DILI. The true burden of ALF is difficult to quantify, but it is the primary indication for liver transplantation in around 8% of cases within Europe.

Answer 4

The cause of ALF is numerous, but drug-induced liver injury (DILI) is the most common reason in Europe. This may be divided into paracetamol or non-paracetamol DILI. The true burden of ALF is difficult to quantify, but it is the primary indication for liver transplantation in around 8% of cases within Europe.

Question 5

ALF is characterised by the presence of coagulopathy (INR > …) and HE. This is usually accompanied by transaminitis (i.e. deranged liver function tests …/…) and hyper… ALF is usually initiated following a severe acute liver injury (ALI).

Answer 5

ALF is characterised by the presence of coagulopathy (INR > 1.5) and HE. This is usually accompanied by transaminitis (i.e. deranged liver function tests ALT/AST) and hyperbilirubinaemia. ALF is usually initiated following a severe acute liver injury (ALI).

Question 6

Acute liver failure (ALF): severe acute liver injury with development of …. (INR >1.5) and hepatic …. within 28 weeks of disease onset. Further classified into hyperacute, acute and subacute.

Question 7

Acute liver injury (ALI): severe acute liver injury from a primary liver aetiology. It is characterised by liver damage (i.e. elevated transaminases) and impaired liver function (e.g. … and … with INR > 1.5). Hepatic … is absent.

Answer 7

Acute liver injury (ALI): severe acute liver injury from a primary liver aetiology. It is characterised by liver damage (i.e. elevated transaminases) and impaired liver function (e.g. jaundice and coagulopathy with INR > 1.5). Hepatic encephalopathy is absent.

Question 8

Secondary liver injury (SLI): similar to ALI but no evidence of a primary liver insult. Examples include severe … or … hepatitis. Management focuses on treating the underlying disease process.

Answer 8

Secondary liver injury (SLI): similar to ALI but no evidence of a primary liver insult. Examples include severe sepsis or ischaemic hepatitis. Management focuses on treating the underlying disease process.

Question 9

The development of … … is the key differentiating factor between ALF and ALI.

Answer 9

The development of hepatic encephalopathy is the key differentiating factor between ALF and ALI.

Question 10

Classifying ALF:
…: HE within 7 days of noticing jaundice. Best prognosis as much better chance of survival and spontaneous recovery.
…: HE within 8-28 days of noticing jaundice
…: HE within 5-12 weeks of noticing jaundice (ALF may be defined up to 28 weeks). Worst prognosis as usually associated with shrunken liver and limited chance of recovery.

Answer 10

Hyperacute: HE within 7 days of noticing jaundice. Best prognosis as much better chance of survival and spontaneous recovery.
Acute: HE within 8-28 days of noticing jaundice
Subacute: HE within 5-12 weeks of noticing jaundice (ALF may be defined up to 28 weeks). Worst prognosis as usually associated with shrunken liver and limited chance of recovery.

Question 11

Define hyperacute liver failure

Answer 11

Hyperacute: HE within 7 days of noticing jaundice. Best prognosis as much better chance of survival and spontaneous recovery.

Question 12

Define acute liver failure

Answer 12

Acute: HE within 8-28 days of noticing jaundice

Question 13

Define subacute liver failure

Answer 13

Subacute: HE within 5-12 weeks of noticing jaundice (ALF may be defined up to 28 weeks). Worst prognosis as usually associated with shrunken liver and limited chance of recovery.

Question 14

HE occurring more than … weeks after onset of jaundice is categorised as chronic liver disease. Usually presenting with decompensated chronic liver disease (dCLD) or acute on chronic liver failure (ACLF) depending on the severity of illness

Answer 14

HE occurring more than 28 weeks after onset of jaundice is categorised as chronic liver disease. Usually presenting with decompensated chronic liver disease (dCLD) or acute on chronic liver failure (ACLF) depending on the severity of illness

Question 15

What is the most common cause of acute liver failure in europe?

Answer 15

Across Europe, drug induced liver injury is the most common cause of ALF.

Question 16

Worldwide, the most common aetiology is … (E.g. hepatitis A, B, E)

Answer 16

Worldwide, the most common aetiology is viral (E.g. hepatitis A, B, E)

Question 17

List primary causes of ALF

Answer 17

Viruses (A, B, E)
Paracetamol
Non-paracetamol medications (e.g. Statins, Carbamazepine, Ecstasy)
Toxin-induced (e.g. Amanita phalloides - death cap mushroom that contains amatoxins and phallotoxins)
Budd-chiari syndrome
Pregnancy-related (e.g. fatty liver of pregnancy, HELLP syndrome)
Autoimmune hepatitis
Wilson’s disease

Question 18

List secondary causes of ALF

Answer 18

Ischaemic hepatitis
Liver resection (post-hepatectomy liver failure)
Severe infection (e.g. malaria)
Malignant infiltration (e.g. lymphoma)
Heat stroke
Haemophagocytic syndromes

Question 19

Is an emergency liver transplant an option in secondary causes of ALF?

Answer 19

No - primary only

Question 20

The exact pathophysiology of ALF depends on the underlying aetiology leading to liver dysfunction. Most cases of ALF are associated with a direct insult to the liver leading to massive … … (death of tissue) and/or … (programmed cell death), which prevents the liver from carrying out its normal function.

Answer 20

The exact pathophysiology of ALF depends on the underlying aetiology leading to liver dysfunction. Most cases of ALF are associated with a direct insult to the liver leading to massive hepatocyte necrosis (death of tissue) and/or apoptosis (programmed cell death), which prevents the liver from carrying out its normal function.

Question 21

As ALF progresses it can lead to a hyperdynamic circulatory state with low systemic vascular resistance due to a profound inflammatory response. Collectively, this causes … … perfusion and …-… failure. Patients also develop significant metabolic derangements (e.g. hypoglycaemia, electrolyte derangement) and are at increased risk of …

Answer 21

As ALF progresses it can lead to a hyperdynamic circulatory state with low systemic vascular resistance due to a profound inflammatory response. Collectively, this causes poor peripheral perfusion and multi-organ failure. Patients also develop significant metabolic derangements (e.g. hypoglycaemia, electrolyte derangement) and are at increased risk of infection.

Question 22

Marked … oedema occurs, which is a major cause of morbidity and mortality in ALF. This is thought to be due to hyperammonaemia causing cytotoxic oedema and increased … blood flow that disrupts … autoregulation.

Answer 22

Marked cerebral oedema occurs, which is a major cause of morbidity and mortality in ALF. This is thought to be due to hyperammonaemia causing cytotoxic oedema and increased cerebral blood flow that disrupts cerebral autoregulation.

Question 23

ALF is characterised by …, confusion and ..

Answer 23

ALF is characterised by jaundice, confusion and coagulopathy.

Question 24

The key clinical features in ALF are jaundice and HE. HE may manifest as …, … … status, … (i.e. flapping tremor) and/or … Jaundice is usually obvious by looking at the skin and sclera.

Answer 24

The key clinical features in ALF are jaundice and HE. HE may manifest as confusion, altered mental status, asterixis (i.e. flapping tremor) and/or coma. Jaundice is usually obvious by looking at the skin and sclera.

Question 25

What are the key clinical features of ALF ?

Answer 25

Jaundice and HE

Question 26

In patients with suspected ALI or ALF, it is essential to look for any features of chronic liver disease (e.g. … …, palmar …, …) that may suggest the first presentation of decompensated … rather than ALF.

Answer 26

In patients with suspected ALI or ALF, it is essential to look for any features of chronic liver disease (e.g. spider naevi, palmar erythema, leuconychia) that may suggest the first presentation of decompensated cirrhosis rather than ALF.

Question 27

Signs & symptoms of ALF

Answer 27

Altered mental status
Confusion
Asterixis: flapping tremor suggestive of HE
Jaundice
Right upper quadrant pain (variable)
Hepatomegaly
Ascites
Bruising (coagulopathy)
GI bleeding: haematemesis, melaena
Hypotension and tachycardia: reduce systemic vascular resistance and hyperdynamic circulation
Raised intracranial pressure: papilloedema, bradycardia, hypertension, low GCS

Question 28

Hepatic encephalopathy

The severity of HE can be graded using the … … criteria

Answer 28

Hepatic encephalopathy

The severity of HE can be graded using the West Haven criteria

Question 29

The severity of HE can be graded using the West Haven criteria:

Grade I: change in behaviour with minimal change in level of …. May have mild … or ….
Grade II: gross disorientation, drowsiness, … and inappropriate behaviour
Grade III: marked confusion, incoherent speech, sleeping most of the time but rousable to … stimuli. … less noticeable, elements of rigidity.
Grade IV: … that is … to verbal or painful stimuli. Evidence of decorticate or decerebrate posturing.

Answer 29

Hepatic encephalopathy

The severity of HE can be graded using the West Haven criteria:

Grade I: change in behaviour with minimal change in level of consciousness. May have mild asterixis or tremor.
Grade II: gross disorientation, drowsiness, asterixis and inappropriate behaviour
Grade III: marked confusion, incoherent speech, sleeping most of the time but rousable to verbal stimuli. Asterixis less noticeable, elements of rigidity.
Grade IV: coma that is unresponsive to verbal or painful stimuli. Evidence of decorticate or decerebrate posturing.

Question 30

Early transfer to a …. … is imperative in patients with ALF.

Answer 30

Early transfer to a transplant centre is imperative in patients with ALF.

Question 31

The initial work-up for a patient with suspected ALF involves formal clinical assessment alongside urgent blood tests, non-invasive liver screen and imaging. Collectively, this helps to differentiate ALI from ALF (by the presence of …), determine the aetiology, investigate for underlying cirrhosis and assess how urgently they need to be transferred to a transplant centre for further work-up.

Answer 31

The initial work-up for a patient with suspected ALF involves formal clinical assessment alongside urgent blood tests, non-invasive liver screen and imaging. Collectively, this helps to differentiate ALI from ALF (by the presence of HE), determine the aetiology, investigate for underlying cirrhosis and assess how urgently they need to be transferred to a transplant centre for further work-up.

Question 32

Urgent blood tests for ALF:

Answer 32

Full blood count
Urea & electrolytes
Liver function tests: including conjugated and unconjugated bilirubin
Bone profile
Blood glucose
Arterial ammonia
Arterial blood gas (pH and lactate)
Coagulation: urgent INR
Lactate dehydrogenase
Lipase/amylase: pancreatitis complication of ALF
Blood cultures: sepsis is major cause of morbidity and mortality

Question 33

What is a non-invasive liver screen?

Answer 33

This refers to a series of tests that are critical to determine the aetiology (e.g. viral, autoimmune). If they are all negative, an alternative cause for ALF needs to be determined (e.g. DILI).

Toxicology screen: serum/urine
Paracetamol serum level
Autoimmune markers: ANA, autoantibodies, immunoglobulins, ANCA
Viral screen:
Hepatitis A: anti-HAV IgM
Hepatitis B: HBsAg, anti-HBc IgM +/- HBV DNA levels
Hepatitis C: anti-HCV (unlikely to cause ALF - may be co-infected)
Hepatitis D: if positive for HBV
Hepatitis E: anti-HEV IgM +/- HEV RNA levels
Other: CMV, EBV, HSV, VZV, Parvovirus

Question 34

Imaging for ALF

Answer 34

Diagnostic imaging of the liver is essential as part of the aetiological work up with doppler ultrasound to assess the patency of the hepatic and portal veins. It is also needed to look for evidence of pre-existing cirrhosis. Cross-sectional imaging of the abdomen (e.g. CT abdomen and pelvis) may be required to examine the liver architecture, volume, vascular integrity and exclude complications such as pancreatitis.

Question 35

ALI vs ALF - what is the key differentiation?

Answer 35

Development of HE - it is important to carefully screen for HE, which may involve clinical assessment, cognitive tests, arterial ammonia and electroencephalogram (EEG)

Question 36

HE can alter … and lead to …. Therefore, patients need to be regularly reviewed and considered for early transfer to intensive care (e.g. ≥grade 2 HE) where physicians are skilled in … … Even subtle alterations in mental status could indicate development of life-threatening ALF within the immediate future.

Answer 36

HE can alter consciousness and lead to coma. Therefore, patients need to be regularly reviewed and considered for early transfer to intensive care (e.g. ≥grade 2 HE) where physicians are skilled in airway management. Even subtle alterations in mental status could indicate development of life-threatening ALF within the immediate future.

Question 37

Contraindications to transplant:

Patients with ALF may be considered for superurgent liver transplantation. It is therefore important to determine factors that would affect the decision to undergo transplantation. This may include previous …., which would indicate …. … rather than ALF, heavy . .., significant …-… (e.g. major cardiac or respiratory disease) or terminal … (e.g. cancer).

Answer 37

Patients with ALF may be considered for superurgent liver transplantation. It is therefore important to determine factors that would affect the decision to undergo transplantation. This may include previous cirrhosis, which would indicate decompensated cirrhosis rather than ALF, heavy alcohol use, significant co-morbidities (e.g. major cardiac or respiratory disease) or terminal illness (e.g. cancer).

Question 38

Paracetamol and hyperacute aetiology:

Arterial pH: … on day 2 or >… thereafter
Renal: Oliguria or elevated …
Mental status: Altered consciousness (i.e. …)
Glucose: …glycaemia
Lactate: ….. lactate unresponsive to … ….

Answer 38

Arterial pH: <7.30 or bicarbonate <18 mmol/L
INR: >3.0 on day 2 or >4.0 thereafter
Renal: Oliguria or elevated creatinine
Mental status: Altered consciousness (i.e. HE)
Glucose: Hypoglycaemia
Lactate: Elevated lactate unresponsive to fluid resuscitation

Question 39

Non-paracetamol aetiology:

Arterial pH:  ….
Renal: Oliguria or … …. …
Serum sodium:  < … mmol/L
Mental status: …
Metabolic: …glycaemia or metabolic …
Bilirubin: >. …umol/L
Imaging: … liver size

Answer 39

Arterial pH:  <7.30 or bicarbonate <18 mmol/L
INR: >1.8
Renal: Oliguria or acute kidney injury
Serum sodium:  < 130 mmol/L
Mental status: HE
Metabolic: hypoglycaemia or metabolic acidosis
Bilirubin: >300 umol/L
Imaging: Shrinking liver size

Question 40

The …. …. criteria is commonly used to help select patients to undergo liver transplantation.

Answer 40

The King’s college criteria is commonly used to help select patients to undergo liver transplantation.

Question 41

Patients with ALF can be considered for … listing for an emergency liver transplantation if there are no major contraindications and the patient is deemed stable enough to undergo a major operation. This is a complex decision that takes place between hepatologists, intensive care physicians and transplant surgeons.

Answer 41

Patients with ALF can be considered for superurgent listing for an emergency liver transplantation if there are no major contraindications and the patient is deemed stable enough to undergo a major operation. This is a complex decision that takes place between hepatologists, intensive care physicians and transplant surgeons.

Question 42

The overall one year survival following emergency liver transplantation is around ..%.

Answer 42

The overall one year survival following emergency liver transplantation is around 80%.

Question 43

Factors associated with poor prognosis and need for transplantation include:

Answer 43

Encephalopathy: any evidence of HE should prompt critical care assessment
Extrahepatic organ failure: particularly acute kidney injury
Adverse aetiology: indeterminate aetiology associated with poor survival without transplant
Type of presentation: subacute ALF associated with poor survival without transplant
Biochemical markers: the significance depends on the underlying aetiology

Question 44

Transplantation should be considered in those patients fulfilling the King’s College criteria (paracetamol criteria):

Arterial pH: < … after resuscitation and > 24 h since ingestion
Lactate: > … mmol/L after resuscitation, OR
The 3 following criteria:
Hepatic encephalopathy ≥ grade …
Serum … > 300 umol/L
INR > …

Answer 44

Arterial pH: < 7.3 after resuscitation and > 24 h since ingestion
Lactate: > 3 mmol/L after resuscitation, OR
The 3 following criteria:
Hepatic encephalopathy ≥ grade 3
Serum creatinine > 300 umol/L
INR > 6.5

Question 45

Transplantation should be considered in those patients fulfilling the King’s College criteria (Non-paracetamol)

INR: > …, OR
3 out of 5 following criteria:
Aetiology: indeterminate aetiology hepatitis, drug-induced hepatitis
Age: < … years or > … years
Jaundice: Interval jaundice-encephalopathy > 7 days
Bilirubin: > … umol/L
INR: > …

Answer 45

INR: > 6.5, OR
3 out of 5 following criteria:
Aetiology: indeterminate aetiology hepatitis, drug-induced hepatitis
Age: < 10 years or > 40 years
Jaundice: Interval jaundice-encephalopathy > 7 days
Bilirubin: > 300 umol/L
INR: > 3.5

Question 46

Management principles - ALF (cardiac)

Answer 46

Cardiovascular: fluid resuscitation +/- use of inotropic agents (increase vascular tone and contractility)

Question 47

Management principles - ALF (Respiratory)

Answer 47

Respiratory: intubation and ventilation may be needed for HE or respiratory failure. Consider paracentesis to improve oxygenation. Chest physiotherapy. Extracorporeal membrane oxygenation (ECMO) may be needed in selected patients.

Question 48

Management principles - ALF (gastrointestinal)

Answer 48

Gastrointestinal: nutrition (NG feeding +/- total parenteral nutrition), gastric ulcer prophylaxis (proton pump inhibitor), and assess for pancreatitis. Manage GI bleeding as needed.

Question 49

Management principles - ALF (metabolic)

Answer 49

Hypoglycaemia: maintain blood glucose level 8-11 mmol/L
Hyponatraemia: maintain serum sodium 140-145 mmol/L. May require hypertonic saline, improves intracerebral pressure.
Acidosis and lactate: used as part of transplant selection criteria
Hypophosphataemia: suggestive of liver regeneration, good prognostic sign. Needs correction.

Question 50

Management principles - ALF (Renal)

Answer 50

acute kidney injury is common. May require renal replacement therapy.

Question 51

Management principles - ALF (Coagulopathy)

Answer 51

imbalance in coagulation (loss of pro and anticoagulation factors with low platelets). No increased bleeding risk. Use blood products if bleeding.

Question 52

Management principles - ALF (Sepsis)

Answer 52

high risk of life-threatening infections including fungal. Early, aggressive treatment of infections with broad spectrum anti-microbials.

Question 53

Management principles - ALF (Neurological)

Answer 53

may require intubation and ventilation for high grade HE due to risk of aspiration. At risk of raised intracranial pressure (ICP). Need specific raised ICP monitoring and management.

Question 54

Management principles - ALF (Liver)

Answer 54

should be assessed and considered for urgent transplantation as discussed.

Question 55

Survival from ALF is greater than …% and around ….% of patients will have spontaneous recovery without need for liver transplantation.

Answer 55

Survival from ALF is greater than 60% and around 55% of patients will have spontaneous recovery without need for liver transplantation.

Question 56

Major complications associated with ALF include sepsis due to marked immune dysfunction and progressive …-… failure, which includes acute kidney injury, metabolic disturbance, haemorrhage (e.g. GI Bleeding) and cerebral dysfunction (e.g. seizures, irreversible brain injury). Cerebral dysfunction is commonly the result of raised … …. Patients are at risk of high output cardiac failure due to low vascular resistance from the widespread … response.

Answer 56

Major complications associated with ALF include sepsis due to marked immune dysfunction and progressive multi-organ failure, which includes acute kidney injury, metabolic disturbance, haemorrhage (e.g. GI Bleeding) and cerebral dysfunction (e.g. seizures, irreversible brain injury). Cerebral dysfunction is commonly the result of raised intracranial pressure. Patients are at risk of high output cardiac failure due to low vascular resistance from the widespread inflammatory response.