Acute and acute-on-chronic liver failure — management and transplantation indications

Overview and Definitions

Liver failure exists on a spectrum from acute presentations in previously healthy individuals to acute decompensation superimposed on established chronic liver disease.

Acute Liver Failure (ALF), also termed fulminant hepatic failure, is characterised by rapid onset of hepatic dysfunction (coagulopathy and encephalopathy) within 26 weeks of the initial insult in a patient with no pre-existing liver disease.

Acute-on-Chronic Liver Failure (ACLF), an acute deterioration in a patient with known chronic liver disease or cirrhosis, precipitated by an identifiable trigger, resulting in organ failure and high short-term mortality.

Decompensated Cirrhosis, the clinical transition from compensated to decompensated cirrhosis is marked by the appearance of variceal haemorrhage, ascites, jaundice, or hepatic encephalopathy. Median survival once decompensated is approximately 2 years.

Aetiology

Acute Liver Failure

Hepatitis A and E, transmitted via the faeco-oral route, are typically self-limiting, although approximately 1-2% of those infected will develop fulminant hepatic failure. Hepatitis B and C are transmitted parenterally and may progress to chronic infection; coinfection with hepatitis D markedly increases the risk of cirrhosis and hepatocellular carcinoma.

Acute-on-Chronic Liver Failure: Common Precipitants

Pathophysiology of Key Complications

Hepatic Encephalopathy

Failure of hepatic clearance leads to accumulation of ammonia and other toxins. Cerebral oedema is a particular risk in ALF; it is less prominent in ACLF. Cerebral oedema may progress to herniation and is a major cause of death in ALF.

Coagulopathy

Reduced synthesis of clotting factors I, II, V, VII, IX, and X, combined with thrombocytopaenia (splenic sequestration) and platelet dysfunction. The INR is both a marker of severity and a component of transplant scoring. Note that routine coagulation tests may not capture the full picture, patients with liver failure often have simultaneous reductions in pro- and anticoagulant factors, resulting in a rebalanced but fragile haemostatic state.

Cardiovascular: Hyperdynamic Circulation

Cirrhosis produces splanchnic vasodilatation (nitric oxide-mediated), resulting in low SVR, compensatory tachycardia, and elevated cardiac output. Effective arterial blood volume is reduced, activating the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system.

$$SVR = \frac{MAP - CVP}{CO} \times 80$$

A low SVR with high CO is the hallmark, complicating vasopressor management.

Hepatorenal Syndrome (HRS)

Renal vasoconstriction secondary to systemic vasodilation and RAAS activation, in the absence of intrinsic renal pathology. HRS type 1 (now termed HRS-AKI) is rapidly progressive; HRS type 2 is associated with refractory ascites.

Hepatopulmonary Syndrome and Portopulmonary Hypertension

• Hepatopulmonary syndrome: intrapulmonary vascular dilatation causing right-to-left shunting and hypoxaemia; characterised by orthodeoxia (worsening $SpO_2$ on sitting upright)
• Portopulmonary hypertension: pulmonary arterial hypertension in the context of portal hypertension; significantly increases perioperative risk

Severity Scoring Systems

Child-Turcotte-Pugh (CTP) Score

• Class A: 5-6 points (well-compensated, ~10% perioperative mortality)
• Class B: 7-9 points (significant compromise, ~30% perioperative mortality)
• Class C: 10-15 points (decompensated, ~75-80% perioperative mortality)

MELD Score

$$MELD = 3.78 \times \ln[Bilirubin\;(mg/dL)] + 11.2 \times \ln[INR] + 9.57 \times \ln[Creatinine\;(mg/dL)] + 6.43$$

• Calculated from bilirubin, INR, and serum creatinine
• Higher scores indicate greater mortality risk and more urgent need for transplantation
• Used to prioritise organ allocation on transplant waiting lists

King's College Criteria (ALF, Paracetamol)

Paracetamol-induced ALF:

• Arterial pH < 7.30 after resuscitation, OR
• All three of: INR > 6.5, creatinine > 300 $\mu$mol/L, and grade III-IV encephalopathy

Non-paracetamol ALF:

• INR > 6.5, OR
• Any three of: age < 10 or > 40 years, aetiology (seronegative hepatitis, drug reaction), jaundice-to-encephalopathy interval > 7 days, INR > 3.5, bilirubin > 300 $\mu$mol/L

Management of Acute Liver Failure

General Supportive Care

Hepatic Encephalopathy and Cerebral Oedema

• Grade III-IV encephalopathy: intubate and consider intracranial pressure (ICP) monitoring
• Head of bed 30°, avoid hypotension (CPP = MAP − ICP; target CPP > 60 mmHg)
• Lactulose (titrate to 2-3 soft stools/day) to reduce ammonia production
• Rifaximin as adjunct (non-absorbable antibiotic reducing gut ammonia production)
• Hypertonic saline (3%) for cerebral oedema; target serum sodium 145-155 mmol/L
• Mannitol 0.5-1 g/kg IV for acute ICP rises if renal function preserved
• Avoid nephrotoxins, benzodiazepines, opioids where possible

Coagulopathy Management

• Do NOT correct coagulopathy with FFP prophylactically, INR is a prognostic marker; its correction masks disease severity and wastes products
• FFP, cryoprecipitate, and platelets indicated for active bleeding or invasive procedures
• Vitamin K IV (phytomenadione 10 mg) if cholestasis may contribute
• Consider recombinant factor VIIa for refractory haemorrhage

Specific Causes

• Paracetamol overdose: N-acetylcysteine (NAC), mainstay treatment; loading dose 150 mg/kg IV over 60 minutes, then infusion; benefits extend beyond acetaminophen toxicity into improving microcirculation in ALF of any cause
• Hepatitis B: antiviral therapy (tenofovir or entecavir)
• Autoimmune hepatitis: corticosteroids (prednisolone 40-60 mg/day) if no infection
• Wilson's disease: chelation therapy; urgent transplant evaluation
• Budd-Chiari: anticoagulation, TIPSS, or transplantation

Management of Acute-on-Chronic Liver Failure (ACLF)

Identify and Treat the Precipitant

Ascites Management

• Dietary sodium restriction (80-120 mmol/day)
• Spironolactone (starting dose 100 mg/day, up to 400 mg/day) ± frusemide (40 mg/day, up to 160 mg/day)
• Therapeutic paracentesis for tense or refractory ascites; albumin replacement 6-8 g per litre drained if >5 L removed
• TIPSS for refractory ascites (contraindicated if encephalopathy, severe portal hypertension with bilirubin >50 $\mu$mol/L, or cardiopulmonary contraindications)

Variceal Prophylaxis

• Non-selective beta-blockade (propranolol or carvedilol) for secondary prophylaxis
• Endoscopic band ligation for oesophageal varices

Indications for Liver Transplantation

Liver transplantation is the definitive management for both acute and chronic liver failure. The liver is the second most commonly transplanted organ after the kidney.

ALF, Transplant Indications

King's College Criteria (above) remain the most widely used prognostic tool. Listing for transplantation should occur early as deterioration can be rapid. The window for transplantation in ALF is narrow.

Chronic Liver Disease / ACLF, Transplant Indications

Contraindications to Transplantation

Five-year patient survival following liver transplantation is approximately 73%.

Anaesthetic Implications

Preoperative Assessment for Patients with Liver Disease

A consultant anaesthetist should consider liver disease severity, functional reserve, and end-organ involvement in all patients. Elective surgery is contraindicated in patients with acute hepatitis or liver failure. Patients with chronic hepatitis can safely undergo elective surgery, but hepatotoxic drugs must be avoided and hepatic perfusion maintained.

CTP class and MELD score predict perioperative mortality risk and guide decision-making regarding the appropriateness of elective, urgent, or emergency surgery.

Drug Considerations

Advanced liver disease impairs elimination of many drugs, requiring dose adjustment:

Intraoperative Monitoring and Management

• Arterial line mandatory for haemodynamic monitoring and serial ABG/glucose/lactate measurement
• Central venous access for vasoactive drug infusion and CVP monitoring; consider PA catheter or TOE for complex cases
• Maintain MAP >65 mmHg (higher if pre-existing portal hypertension)
• Avoid hypoxia, hypercapnia, and hypotension, all increase hepatic ischaemia
• Anticipate massive haemorrhage in patients with coagulopathy and portal hypertension; have cell salvage, massive transfusion protocol, and viscoelastic testing (TEG/ROTEM) available
• Regional anaesthesia: consider if coagulation status permits (INR ≤1.5, platelets ≥80 × $10^9$/L for neuraxial blocks); avoid in severe coagulopathy

Liver Transplantation Anaesthesia: Unique Challenges

Anaesthetic management for liver transplantation is particularly challenging due to:

• Unpredictable, potentially massive blood loss
• Coagulation abnormalities requiring real-time viscoelastic guidance
• Electrolyte and acid-base disturbances (metabolic acidosis, hyperkalaemia with reperfusion)
• Haemodynamic instability, particularly at reperfusion (post-reperfusion syndrome: >30% drop in MAP for >1 minute)
• Pulmonary complications: hepatopulmonary syndrome, portopulmonary hypertension
• Renal dysfunction, patients undergoing liver transplantation are at significant risk for perioperative AKI given pre-existing hepatorenal physiology
• Neurological: encephalopathy, cerebral oedema management

Postoperative Priorities

• Tight glucose control (hepatic gluconeogenesis impaired)
• Continued vasopressor support as required
• Early enteral nutrition
• Lactulose and rifaximin for encephalopathy prophylaxis
• Vigilance for primary non-function of the graft (rising bilirubin, worsening coagulopathy, haemodynamic instability)
• Immunosuppression initiation and monitoring in transplant recipients

Sources

• ANZCA Professional Documents (PS series)
• ANZCA clinical guidelines