Acute liver disease and acute liver failure

At a glance

• Acute liver disease ranges from self-limiting hepatitis to acute liver failure (ALF), a rare (a few hundred cases a year in Australia) and often lethal syndrome in previously healthy people.
• ALF = INR 1.5 or more plus hepatic encephalopathy within 26 weeks of onset, without pre-existing cirrhosis.
• Paracetamol causes about half of ALF in Australia. Give acetylcysteine in paracetamol ALF, and in non-paracetamol ALF with early (grade 1 to 2) encephalopathy.
• Call a liver transplant unit early, at a rising INR, before encephalopathy deepens. Transfer is safest before intubation.

Definitions

Term	Definition
Acute hepatitis	Raised ALT without synthetic failure
Severe acute liver injury	ALT usually over 3 to 10 times ULN with INR 1.5 or more, no encephalopathy
Acute liver failure	INR 1.5 or more plus encephalopathy, within 26 weeks, no cirrhosis

• Wilson disease, vertically acquired hepatitis B and autoimmune hepatitis can count as ALF even with underlying cirrhosis if the illness is recent.
• Decompensation of known cirrhosis is acute-on-chronic liver failure, a different syndrome.

O'Grady classification (jaundice to encephalopathy)

Type	Interval	Typical causes	Cerebral oedema	Transplant-free survival
Hyperacute	Under 7 days	Paracetamol, hepatitis A and E, ischaemia	Common	Best
Acute	1 to 4 weeks	Hepatitis B	Moderate	Intermediate
Subacute	5 to 12 weeks	Idiosyncratic DILI, autoimmune, indeterminate	Rare	Worst

Pitfall: the subacute patient with mild confusion, ascites and a small liver looks like cirrhosis and less sick than the hyperacute patient. They often die without a transplant.

Causes

Cause	Clues and specific treatment
Paracetamol	Very high ALT (often over 3000 U/L), low bilirubin early, acidosis, AKI. Acetylcysteine. Staggered or repeated supratherapeutic doses give low or absent levels
Idiosyncratic DILI	Antibiotics, anti-TB drugs, supplements. Stop all non-essential drugs (see Drug-induced hepatitis)
Hepatitis B	Acute infection or reactivation with chemotherapy or rituximab. Entecavir or tenofovir
Hepatitis A and E	IgM serology, HEV RNA. HEV genotype 1 in pregnancy is severe
HSV, VZV	Pregnancy or immunosuppression, fever, ALT very high with little jaundice. IV aciclovir empirically
Autoimmune hepatitis	Raised IgG, autoantibodies may be absent. Steroids early, before multi-organ failure (see Autoimmune hepatitis)
Wilson disease	Young, Coombs-negative haemolysis, ALP (U/L) to total bilirubin (mg/dL) ratio under 4, which is about under 0.23 with bilirubin in µmol/L, with AST:ALT over 2.2 (Korman 2008). Plasma exchange as a bridge; almost always needs transplant
Ischaemic hepatitis	Hypotension, heart failure; ALT peaks within 1 to 2 days and falls fast
Budd-Chiari	Ascites, hepatomegaly, pain. Doppler, anticoagulation, TIPS
Pregnancy	Acute fatty liver of pregnancy, HELLP. Deliver
Death cap mushroom (Amanita phalloides)	Grows under oaks in Canberra and Victoria in autumn. Delayed vomiting and diarrhoea, false recovery, then ALF. Silibinin, acetylcysteine, charcoal
Malignant infiltration	Lymphoma, breast cancer. Hepatomegaly, very high LDH; transplant contraindicated
Indeterminate	No cause in about 1 in 7; some are unrecognised paracetamol or HEV

Recognition

• Malaise, nausea and jaundice, then encephalopathy. Encephalopathy can precede jaundice in hyperacute disease.
• West Haven grades: 1 subtle changes and reversed sleep; 2 lethargy, disorientation, asterixis; 3 somnolent but rousable, marked confusion; 4 coma.
• Signs of raised intracranial pressure: hypertension, bradycardia, abnormal pupils, decerebrate posturing. Papilloedema is often absent.
• Multi-organ involvement looks like sepsis: vasodilated shock, AKI, lactic acidosis, hypoglycaemia, pancreatitis.

Investigations

• INR, bilirubin, ALT, AST, ALP, albumin, glucose (1 to 2 hourly), arterial lactate, arterial ammonia, blood gas, electrolytes, phosphate, creatinine, lipase, FBC with film.
• Cause: paracetamol level, toxicology screen, HAV IgM, HBsAg and anti-HBc IgM, HCV RNA, HEV IgM and RNA, HSV and VZV PCR, autoimmune serology and IgG, caeruloplasmin with urinary copper, pregnancy test.
• Doppler ultrasound for hepatic and portal veins, liver size and malignancy. CT brain only to exclude other causes; it is insensitive for cerebral oedema.
• Blood group and HIV serology for transplant work-up. Low phosphate is a good sign (regeneration). High phosphate is a bad one.

Management

Everyone

• Discuss with a liver transplant unit once INR is 1.5 or more with any encephalopathy, or INR rising past 2 to 3 in paracetamol toxicity. Australian adult units are in Sydney, Melbourne, Brisbane, Adelaide and Perth, with Auckland in New Zealand.
• IV acetylcysteine in all paracetamol cases, and in non-paracetamol ALF with grade 1 or 2 encephalopathy (Lee 2009: transplant-free survival 52% v 30% in grade 1 to 2, with no benefit in grade 3 to 4).
• ICU for grade 2 or worse encephalopathy. Intubate at grade 3 to 4 to protect the airway.
• Glucose: monitor at least 2-hourly and infuse dextrose for levels under 4 mmol/L.
• Avoid sedatives, NSAIDs and nephrotoxins. Don't use lactulose; it distends the bowel and doesn't help ALF encephalopathy.

Brain

• Cerebral oedema drives much of the mortality in hyperacute ALF. Risk rises with ammonia over about 150 to 200 µmol/L, grade 3 to 4 encephalopathy, younger age and need for vasopressors or RRT.
• Head up 30 degrees, avoid fever, keep PaCO2 normal and serum sodium 145 to 150 mmol/L with hypertonic saline.
• Surges: mannitol or hypertonic saline boluses, short hyperventilation as a bridge.
• Early continuous RRT lowers ammonia even without AKI.

Circulation, kidneys, blood and infection

• Crystalloid, then noradrenaline for MAP 65 mmHg or more (higher if ICP is raised). Consider hydrocortisone in refractory shock.
• Coagulation: don't correct INR unless bleeding or for a procedure. Haemostasis is rebalanced, and INR is a prognostic marker. Give vitamin K once. Platelets and fibrinogen for procedures.
• Give a PPI for stress ulcer prophylaxis.
• Infection is common and often silent. Culture regularly and have a low threshold for broad-spectrum antibiotics and antifungals.
• High-volume plasma exchange improved transplant-free survival in a Danish RCT (Larsen 2016) and is used as a bridge, especially in Wilson disease.

Prognosis and transplant

King's College criteria (O'Grady 1989) predict death without transplant. They are specific but not very sensitive, so failing to meet them doesn't mean the patient is safe.

Paracetamol	Non-paracetamol
Arterial pH under 7.30 after resuscitation, or all of INR over 6.5, creatinine over 300 µmol/L and grade 3 to 4 encephalopathy	INR over 6.5, or three of: age under 10 or over 40, indeterminate or drug cause, jaundice over 7 days before encephalopathy, INR over 3.5, bilirubin over 300 µmol/L

• Lactate (Bernal 2002) added to the paracetamol criteria: over 3.5 mmol/L at 4 hours or over 3.0 mmol/L at 12 hours after resuscitation.
• Other tools: MELD, the Clichy criteria (factor V), and the ALFSG index.
• Super-urgent listing gets national priority for the next suitable liver. One-year survival after transplant for ALF is about 80 to 90%.
• Contraindications: uncontrolled sepsis, irreversible brain injury, malignancy, and in paracetamol overdose, ongoing severe psychiatric risk or substance use (assessed urgently by the transplant team).

Special populations

• Pregnancy: AFLP (third trimester, hypoglycaemia, raised urate, coagulopathy) and HELLP need delivery. HSV and HEV are more severe.
• Older people: over 40 is a poor prognostic sign in the King's criteria, and transplant candidacy is narrower.
• Low body weight, malnutrition and heavy alcohol use increase paracetamol toxicity at therapeutic doses.

Pitfalls

• Pitfall: waiting for a paracetamol level or the nomogram in a late presentation with raised ALT. Start acetylcysteine.
• Pitfall: giving FFP to "fix" the INR before transfer. It obscures prognosis and adds volume.
• Pitfall: sedating an agitated patient with benzodiazepines, masking encephalopathy grade.
• Missing HSV because there was no rash or jaundice.
• Missing Wilson disease in a young adult with haemolysis and a low ALP.
• Using King's criteria to reassure. A patient who misses them can still die.