Acute Liver Failure

Definition of Acute Liver Failure (ALF)

• Acute liver failure (ALF) is characterised by a rapid decline in hepatic function, defined by:
  • Coagulopathy with an international normalised ratio (INR) ≥1.5,
  • Hepatic encephalopathy, indicating altered mental status,
  • Occurring in individuals with no prior history of cirrhosis or known chronic liver disease,
  • With a clinical illness duration of less than 26 weeks.
• Older terms such as fulminant hepatic failure and acute hepatic necrosis have historically been used but are now replaced by the preferred term acute liver failure.
• Both coagulopathy and encephalopathy are essential for diagnosis. Although jaundice is commonly observed and often precedes encephalopathy, it may not be present in all cases—especially in hyperacute presentations.

Diagnostic Distinctions

• ALF may also be diagnosed in patients with previously unrecognised conditions such as:
  • Wilson disease,
  • Vertically transmitted or reactivated hepatitis B,
  • Autoimmune hepatitis, provided the illness has been recognised for fewer than 26 weeks and there is no established chronic liver damage.
• In contrast, patients with acute severe alcohol-associated hepatitis are classified as having acute-on-chronic liver failure, even if recognised within 26 weeks, due to the underlying liver fibrosis from long-term alcohol use.

Temporal Subclassification

• ALF is often subcategorised based on the interval between onset of jaundice and the development of encephalopathy:
  • Hyperacute ALF: <7 days
  • Acute ALF: 7 to 21 days
  • Subacute ALF: >21 days and <26 weeks
• These subtypes differ in clinical profile and prognosis:
  • Hyperacute ALF is commonly associated with cerebral oedema but generally has a more favourable prognosis, often due to causes like paracetamol toxicity or ischaemic hepatopathy.
  • Subacute ALF has a lower incidence of cerebral oedema but a higher likelihood of complications such as renal failure and portal hypertension, and tends to have a poorer prognosis.

Differentiation from Other Conditions

• It is crucial to differentiate ALF from:
  • Decompensated cirrhosis,
  • Acute-on-chronic liver failure,
  • Severe acute hepatitis without encephalopathy.
  • This distinction is important as prognosis and management strategies vary significantly depending on the underlying condition.

Drug-Induced Liver Injury

 Paracetamol (Acetaminophen) Toxicity

• Leading cause of ALF in the UK, US, and other high-income countries.
• In the US, it accounts for ~46% of cases; in the UK, up to 66%.
• Overdose can be intentional (e.g. suicide attempt) or unintentional (therapeutic misadventure or unrecognised multi-drug ingestion).
• Risk is amplified by chronic alcohol use or malnutrition, which depletes hepatic glutathione and increases hepatotoxicity at standard doses.
• Paracetamol may also contribute to cases deemed "indeterminate" where no other cause is found.

Idiosyncratic Drug Reactions

• Account for approximately 11–15% of ALF cases in Western countries.
• Unlike paracetamol, reactions are unpredictable and dose-independent.
• Commonly implicated drug classes:
  • Antibiotics (e.g. ampicillin-clavulanate, ciprofloxacin, isoniazid)
  • Antiepileptics (e.g. phenytoin, valproate)
  • Antidepressants, NSAIDs, statins, and immunosuppressants
• Herbal and dietary supplements are increasingly implicated in non-paracetamol ALF, with some associated with higher transplantation rates and poorer transplant-free survival.

Illicit Drugs and Toxins

• Substances like ecstasy (MDMA), cocaine, and Amanita phalloides mushrooms have well-documented hepatotoxic potential.
• Industrial toxins such as carbon tetrachloride, cyanobacteria, and yellow phosphorus are recognised agents.
• Outbreaks have linked certain commercial supplements (e.g. OxyELITE Pro) to severe hepatic injury and ALF.

Viral Hepatitis

 Hepatitis A and B

• Hepatitis A rarely progresses to ALF (~0.35% of infections), though it remains a known trigger.
• Hepatitis B accounts for ~7–18% of ALF in various cohorts, including reactivation in immunosuppressed individuals.
• Mutant strains of hepatitis B (precore or pre-S) can present without traditional serological markers, contributing to diagnostic uncertainty.

Hepatitis C

• Rarely causes ALF on its own; more frequently implicated when coinfection with hepatitis B is present.

Hepatitis D

• Requires concomitant hepatitis B for infection.
• Coinfection carries a higher risk of fulminant progression than superinfection.

Hepatitis E

• Common cause of ALF in South and Southeast Asia, with high mortality rates in pregnant women (15–25%).
• Accounts for the majority of ALF cases in regions such as Bangladesh and India.
• Largely absent in the West, but should be considered in returned travellers from endemic regions.

Other Viruses

• Herpes simplex virus (HSV), varicella zoster virus, Epstein-Barr virus, cytomegalovirus, and adenovirus are uncommon but important causes, particularly in immunocompromised hosts.

Autoimmune Hepatitis

• Responsible for up to 7% of ALF cases.
• More common in women.
• Presentation may be indistinguishable from drug-induced or viral hepatitis.

Ischaemic Hepatopathy and Vascular Causes

 Ischaemic Hepatitis

• Often secondary to hypoperfusion due to cardiac failure, septic shock, or major haemorrhage.

Budd-Chiari Syndrome

• Hepatic vein thrombosis impairs hepatic outflow and may precipitate ALF.

Veno-Occlusive Disease

• Usually occurs post-chemotherapy or bone marrow transplantation.

Portal or Hepatic Artery Thrombosis

• May cause massive infarction and sudden liver failure, especially post-transplant.

Metabolic and Genetic Disorders

• Wilson disease (notably rapid progression and poor prognosis without transplantation)
• Alpha-1 antitrypsin deficiency
• Tyrosinaemia
• Fructose intolerance
• Galactosaemia
• Lecithin-cholesterol acyltransferase deficiency
• Reye syndrome (typically in children)

Pregnancy-Associated Causes

 Acute Fatty Liver of Pregnancy (AFLP)

• Typically arises in the third trimester.
• Associated with preeclampsia in ~50% of cases.
• Rare but potentially fatal; occurs in ~0.008% of pregnancies.

HELLP Syndrome

• Occurs in 0.1–0.6% of pregnancies.
• May result in liver failure, particularly in conjunction with severe haemolysis and thrombocytopenia.

Hepatitis E

• As noted, carries significant risk in pregnant women and should be considered in endemic settings.

Malignancy and Infiltrative Disease

• Extensive infiltration of the liver by malignancies such as:
  • Lymphoma
  • Leukaemia
  • Breast, lung, or melanoma metastases
• Rare but important differential in patients presenting with acute liver dysfunction and no history of liver disease.

Miscellaneous Causes

• Heat stroke
• Sepsis
• Partial hepatectomy with inadequate remnant volume
• Hemophagocytic lymphohistiocytosis (typically in children)
• Adult-onset Still’s disease
• Graft non-function after liver transplantation

Hepatocyte Injury and Cell Death

 Necrosis and Apoptosis

• Hepatocyte death in ALF is a complex interplay between necrosis (uncontrolled cell death with inflammation) and apoptosis (programmed cell death).
• Both mechanisms may be present simultaneously, varying in prominence depending on the underlying cause.

Non-necrotic ALF

• In certain conditions (e.g. Reye’s syndrome, acute fatty liver of pregnancy), liver failure may occur in the absence of widespread hepatocellular necrosis, suggesting mitochondrial dysfunction and microvesicular steatosis as alternative pathogenic mechanisms.

Paracetamol-Induced Hepatotoxicity

 Metabolic Pathway

• Paracetamol is mainly conjugated in the liver via glucuronidation and sulfation.
• A minor fraction is oxidised by cytochrome P450 enzymes (especially CYP2E1) to form the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI).

Toxicity Mechanism

• Under normal conditions, NAPQI is neutralised by conjugation with hepatic glutathione.
• In overdose situations, glutathione stores are rapidly depleted, leading to accumulation of NAPQI which binds to cellular proteins and causes hepatocyte death via oxidative stress and mitochondrial injury.

Modifying Factors

• Chronic alcohol use induces CYP2E1 and depletes glutathione, predisposing to hepatotoxicity even at therapeutic doses.
• Fasting, malnutrition, and concurrent use of enzyme-inducing drugs (e.g. barbiturates) further increase vulnerability.

Cerebral Oedema and Intracranial Hypertension

• A major cause of mortality in ALF is cerebral oedema, often secondary to intracranial hypertension (ICH).

Hyperammonaemia plays a central role

• Ammonia is metabolised to glutamine by astrocytes.
• Glutamine accumulation increases osmotic pressure within astrocytes, resulting in cytotoxic oedema.

Cytotoxic Oedema

• Caused by impaired cellular osmoregulation.
• Astrocyte swelling is a consistent pathological finding in ALF.

Vasogenic Factors

• Increased cerebral blood flow due to disrupted autoregulation contributes to oedema.
• High levels of systemic nitric oxide act as vasodilators, exacerbating blood-brain barrier permeability.

Inflammatory Cytokines

• Elevated serum levels of TNF-α, IL-1, IL-6, and bacterial endotoxins promote systemic inflammation, which may worsen cerebral and systemic complications.

Systemic Involvement and Multiorgan Failure

• ALF triggers a hyperdynamic circulatory state, resembling sepsis, with:
  • Low systemic vascular resistance,
  • Hypotension,
  • Impaired tissue perfusion.
• This leads to secondary injury of extrahepatic organs including the kidneys (acute tubular necrosis), lungs (acute respiratory distress syndrome), and heart.
• The cytokine storm and endothelial dysfunction further exacerbate multiorgan injury.

Biomarker and Regeneration Research

• Ongoing studies aim to identify biomarkers of hepatocyte apoptosis and regeneration to predict prognosis and guide therapy.
• Understanding the regenerative capacity of residual hepatocytes is critical, especially when evaluating suitability for liver transplantation or bridging therapies.

Incidence and Global Distribution

• Acute liver failure (ALF) is a rare condition in developed countries, with an estimated incidence of fewer than 10 cases per million people annually.
• In the United States, the annual number of ALF cases is approximately 2,000, while in the UK and other parts of Europe, incidence rates are similarly low.
• In contrast, higher rates are reported in developing regions due to endemic infections such as hepatitis E and hepatitis B virus (HBV), including HBV superinfection with hepatitis delta virus (HDV), particularly in parts of Asia, Africa, the Middle East, and Central America.

Aetiological Trends by Region

• In high-income countries (e.g., the US, UK, Australia):
  • Drug-induced liver injury is the leading cause of ALF, accounting for over 50% of cases.
  • Paracetamol (acetaminophen) toxicity is the predominant cause, responsible for around 42–66% of cases depending on the region.
  • Other notable causes include idiosyncratic drug reactions, autoimmune hepatitis, HBV, Wilson disease, acute fatty liver of pregnancy, and HELLP syndrome.
• In developing regions:
  Viral hepatitis is the major contributor, particularly:
  • HBV in Japan and sub-Saharan Africa.
  • Hepatitis E virus (HEV) in India, Bangladesh, and Mexico, especially in pregnant women where mortality can reach 25%.

Demographics and Population Characteristics

 Sex Distribution

• ALF predominantly affects women, who comprise around 67–73% of reported cases.
• This higher prevalence may be linked to autoimmune liver disease and viral hepatitis E, which disproportionately affect women.

Age Distribution

• The mean age of affected adults is approximately 38 years (range 17–79 years).
• Outcomes tend to be worse in individuals under 10 or over 40 years of age, suggesting an age-related vulnerability.

Ethnic Distribution (US Data)

• White: 74%
• Hispanic: 10%
• Asian: 5%
• Black: 3%
• Latin American and other groups: 2%

Outcomes and Prognosis

• Data from the US Acute Liver Failure Study Group (ALFSG), which includes over 2,000 adult patients across more than 30 centres, reveals:
  • Spontaneous recovery without transplantation: ~45%
  • Liver transplantation performed: ~25%
  • Overall mortality rate: ~30%
• Paediatric ALF registries, drawing data from US, Canadian, and UK centres, show comparable trends in terms of severity and transplantation rates.

Survival Improvements

• Recent decades have seen enhanced short-term survival and transplant-free survival, likely due to improved early recognition, intensive care strategies, and better prognostic tools.

Key Historical Elements to Elicit

Temporal Profile

• Date of onset of jaundice and encephalopathy.
• Interval between jaundice and encephalopathy helps classify ALF (hyperacute, acute, subacute) and informs prognosis.

Drug Exposure

• Paracetamol use: Ask about both therapeutic use and overdose, especially involving combination products with opioids or diphenhydramine.
• Other hepatotoxic drugs: Include antiepileptics, antibiotics, NSAIDs, antidepressants, and anaesthetic agents.
• Herbal and dietary supplements: Widely implicated in idiosyncratic drug-induced liver injury and associated with poor transplant-free survival.

Alcohol Use

• Chronic alcohol misuse increases susceptibility to paracetamol-induced liver injury, even at therapeutic doses.
• A key risk factor for unintentional overdose and worsened prognosis in both paracetamol and non-paracetamol ALF.
• Increases vulnerability to viral hepatitis-associated ALF.

Nutritional Status and Fasting

• Malnutrition and fasting are associated with glutathione depletion, enhancing paracetamol toxicity risk.

Psychiatric History

• Depression or suicidal ideation: Up to 50% of ALF cases from paracetamol in the US are intentional overdoses.
• Co-prescription of antidepressants is common in this cohort, and recurrent suicidal behaviour may affect transplant eligibility.

Illicit Drug Use

• Intravenous drug use may signal exposure to hepatitis B or C.
• Stimulants like MDMA and cocaine may directly induce hepatotoxicity or cause ischaemic hepatitis.

Hepatitis Risk Factors

• Travel to endemic areas (e.g. South Asia, Middle East, Central America),
• Sexual contact,
• History of transfusions,
• Occupational exposure,
• Body piercings or tattoos.

Pregnancy

• Critical due to association with ALF in:
  • Hepatitis E infection (particularly in second and third trimesters),
  • Acute fatty liver of pregnancy (AFLP),
  • HELLP syndrome.
• History should include trimester, any recent symptoms suggestive of preeclampsia, and previous liver-related pregnancy complications.

Family History

• Particularly for Wilson disease or other hereditary liver disorders.

Toxin Exposure

• Ingestion of hepatotoxins such as Amanita phalloides mushrooms, organic solvents, or phosphorus-containing fireworks.

Symptom Complexes and Indicators of Complications

• Jaundice: A cardinal feature. Onset and progression help characterise ALF subtype.
• Hepatic encephalopathy: Timing, mental status changes, and use of West Haven Criteria for grading (1–4).
• Nausea, vomiting, malaise, and abdominal pain: Non-specific but commonly reported.
• Signs of cerebral oedema (collateral history if not directly observable): Recent confusion, headaches, seizures, or posturing may suggest raised intracranial pressure.
• Bleeding or infection symptoms: Suggest coagulopathy or sepsis, respectively.

Important Risk Factors Identified Through History

• Alcohol misuse: Strongly associated with poor prognosis and greater toxicity risk.
• Female sex: More susceptible to drug-induced ALF and viral hepatitis complications.
• Age >40 years: Increased incidence of unintentional overdose and poorer outcomes.
• Chronic pain and polypharmacy: Risk of unintentional paracetamol overdose.
• Chronic hepatitis B or C infection: Increases ALF risk, especially with superinfection or reactivation.
• HIV co-infection: May worsen disease course in chronic hepatitis C patients.
• Wilson disease: Consider especially in young patients with intravascular haemolysis, unexplained coagulopathy, and renal failure.

Negative History Features Supporting Diagnosis

• Absence of chronic liver disease features: No prior ascites, encephalopathy, or variceal bleeding.
• No splenomegaly, spider angiomata, palmar erythema, or ascites: Makes decompensated cirrhosis less likely.

General Appearance and Vital Signs

 Hypotension and Tachycardia

• Common in ALF due to systemic vasodilation and a hyperdynamic circulation that mimics septic shock.
• Haemodynamic instability may also reflect sepsis or adrenal insufficiency.

Fever

• May indicate superimposed infection, especially spontaneous bacterial peritonitis or pneumonia.

Skin and Mucosal Signs

 Jaundice

• A cardinal feature; scleral icterus is usually visible.
• Presence and timing relative to encephalopathy is helpful for prognostication.

Petechiae, ecchymoses, bleeding

• May indicate coagulopathy; spontaneous bruising or mucosal bleeding suggests severe clotting factor deficiency.

Absence of spider angiomata, palmar erythema, or caput medusae

• Supports diagnosis of ALF over chronic liver disease.

Neurological Assessment

 Hepatic Encephalopathy

• A defining feature of ALF. Careful grading is critical for prognostication.
• Graded using the West Haven Criteria:
  • Grade 1: Mild confusion, reversed sleep-wake cycle.
  • Grade 2: Lethargy, disorientation, asterixis.
  • Grade 3: Somnolence, gross disorientation, hyperreflexia.
  • Grade 4: Coma.
• Asterixis, hyperreflexia, Babinski sign, and extrapyramidal signs (e.g. bradykinesia, dysarthria) may be observed.

Signs of Cerebral Oedema and Raised Intracranial Pressure

• Occur in advanced encephalopathy, particularly in hyperacute ALF.
• Includes decerebrate posturing, abnormal pupillary reflexes, papilloedema, muscular rigidity, hypertension, and bradycardia.

Abdominal Examination

 Right Upper Quadrant Tenderness

• May occur in acute hepatitis, congestive hepatopathy, or Budd-Chiari syndrome.

Liver Span

• A small liver may suggest extensive hepatic necrosis.
• Hepatomegaly may be observed in viral hepatitis, heart failure, or malignancy.

Ascites

• Uncommon in ALF, but its sudden onset may indicate Budd-Chiari syndrome or subacute liver failure.
• Ascites in the absence of other signs of chronic liver disease may be the first clue to vascular outflow obstruction.

Gastrointestinal Findings

 Gastrointestinal Bleeding

• Haematemesis or melena may occur due to severe coagulopathy, stress ulcers, or varices if there is previously unrecognised chronic liver disease.

Respiratory and Cardiovascular Examination

 Pulmonary Findings

• May show signs of aspiration pneumonia or pulmonary oedema.
• Consider acute respiratory distress syndrome (ARDS) in severe ALF.

Cardiovascular Signs

• Tachycardia and low systemic vascular resistance are characteristic.
• Must exclude cardiogenic causes or superimposed sepsis.

Features Suggestive of Alternative or Underlying Conditions

 Absence of splenomegaly

• Supports diagnosis of ALF over chronic liver disease.

Signs of chronic liver disease (ascites, spider naevi, palmar erythema)

• Absent in true ALF.

Stigmata of systemic disease

• Look for signs suggestive of autoimmune disease, viral exanthem, or malignancy.

Special Considerations

 Wilson Disease

• May present with Coombs-negative haemolytic anaemia, hypoglycaemia, renal dysfunction, and encephalopathy in young patients.
• Kayser-Fleischer rings may be visible on slit-lamp exam.

Pregnancy-Related Disorders

• Ascertain gestational age; AFLP and HELLP syndrome typically occur in the third trimester.
• Features may include hypertension, proteinuria, and right upper quadrant pain.

Initial Laboratory Tests

Liver Function Tests (LFTs)

• AST/ALT
  • Typically elevated.
  • Values >10,000 U/L suggest paracetamol toxicity.
• ALP
  • Often normal or mildly elevated in hepatocellular injury.
• Bilirubin
  • Elevated in most cases.
  • Bilirubin >4 mg/dL in paracetamol toxicity suggests poor prognosis.
• Patterns of injury
  • R-value helps differentiate hepatocellular (R ≥5), cholestatic (R ≤2), or mixed injury.

Coagulation Studies

• INR/PT
  • Coagulopathy (INR >1.5) is diagnostic for ALF and correlates with poor prognosis.
  • Factor V levels <30% indicate worse outcomes, especially in non-paracetamol cases.

Basic Metabolic Panel

• Renal function
  • Creatinine and urea levels may be elevated due to acute kidney injury or hepatorenal syndrome.
• Electrolytes
  • Monitor for hypokalaemia, hypophosphataemia, hypomagnesaemia, and hyponatraemia.

Full Blood Count (FBC)

• Anaemia
  • May be present in ALF due to Wilson disease (often Coombs-negative haemolysis).
• Leukocytosis
  • May suggest systemic inflammation or infection.
• Thrombocytopenia
  • Associated with advanced disease or sepsis.

Blood Glucose

• Hypoglycaemia
  • Common due to impaired gluconeogenesis and glycogenolysis.

Serum Ammonia

• Elevated in hepatic encephalopathy.
• Levels >200 µmol/L are predictive of cerebral oedema.

Serum Lactate

• Elevated levels at 4 hours (>3.5 mmol/L) and 12 hours (>3.0 mmol/L) post-resuscitation predict poor prognosis in paracetamol-induced ALF.

Serum Phosphate

• Low levels
  • May indicate early liver regeneration.
• Elevated levels
  • Suggest impaired hepatic function.

Autoimmune Markers

• ANA, ASMA, Immunoglobulins
  • Should be checked if autoimmune hepatitis is suspected.

Viral Serologies

• Screen for hepatitis A, B, C, and E, as well as HSV, EBV, CMV, and VZV where relevant.
• Use PCR if serologies are negative and suspicion remains high.

Paracetamol Level and Protein Adducts

• Paracetamol levels
  • May be low on delayed presentation.
• Protein adducts
  • When available, are specific markers of toxicity.

Pregnancy Test

• Serum beta-hCG
  • Essential in all women of reproductive age to evaluate for pregnancy-related liver conditions.

Imaging and Special Tests

Abdominal Ultrasound with Doppler

• Assesses for cirrhosis, biliary obstruction, Budd-Chiari syndrome (hepatic vein thrombosis), and malignancy.
• Doppler flow studies evaluate hepatic and portal vessel patency.

CT or MRI Abdomen

• Consider for detailed liver anatomy, particularly when ultrasound is inconclusive or transplant workup is underway.
• Avoid contrast if renal dysfunction is present.

CT Head

• Recommended in grade 3–4 encephalopathy to assess for cerebral oedema or exclude haemorrhagic lesions.

Transcranial Doppler

• May guide management of intracranial pressure in advanced encephalopathy.

Arterial Blood Gases

• May reveal metabolic acidosis (especially in paracetamol toxicity) or respiratory alkalosis due to hyperventilation.

Blood Cultures

• Obtain early, especially if fever or leukocytosis is present. Infection is common and increases mortality.

Additional Biomarkers

• Alcohol use
  • Ethyl glucuronide or phosphatidylethanol.
• Wilson Disease
  • Low ceruloplasmin.
  • Elevated serum copper and 24-hour urinary copper (>100 µg/day).
  • Alkaline phosphatase:bilirubin ratio <4 and AST:ALT ratio >2.2.
  • Slit-lamp exam for Kayser-Fleischer rings.
  • Hepatic copper levels (via biopsy, if indicated).

Specialised Investigations

Liver Biopsy

• Transjugular approach preferred due to bleeding risk.
• Useful if autoimmune hepatitis, lymphoma, herpes hepatitis, or infiltrative malignancy is suspected.
• Patterns
  • Panlobular necrosis: Viral or idiosyncratic DILI.
  • Centrilobular necrosis: Paracetamol.
  • Microvesicular steatosis: Reye syndrome, valproate, or AFLP.
  • Copper accumulation: Wilson disease.

EEG

• May help differentiate hepatic encephalopathy from seizures or non-convulsive status

Severe Acute Hepatitis

 Key Features

• Patients may exhibit jaundice and coagulopathy, raising concern for ALF.
• However, absence of hepatic encephalopathy excludes the diagnosis of ALF.

Differentiation

• Monitor closely for progression to ALF or subacute liver failure.
• Mental status remains normal; no progression through the West Haven grading of encephalopathy.

West Haven Criteria for Encephalopathy

• Grade 1: Subtle cognitive impairment, sleep disturbance, anxiety.
• Grade 2: Lethargy, disorientation for time, asterixis.
• Grade 3: Somnolence, marked confusion, hyperreflexia.
• Grade 4: Coma.

Cholestasis

 Key Features

• Jaundice due to intrahepatic or extrahepatic biliary obstruction.
• Cholangitis may present with fever, right upper quadrant pain, and shock in acute obstruction.

Differentiation

• Normal INR and absence of encephalopathy distinguish cholestasis from ALF.
• Vitamin K administration may normalise PT/INR in cholestasis with fat-soluble vitamin malabsorption.
• Imaging (e.g., ultrasound) can identify biliary dilation or obstruction.

Haemolysis

 Key Features

• Jaundice predominantly due to elevated unconjugated (indirect) bilirubin.
• Typically occurs in absence of liver dysfunction.

Differentiation

• No coagulopathy or hepatic encephalopathy.
• Peripheral smear may show schistocytes or sickled cells.
• Coombs test positive in autoimmune haemolysis; negative in Wilson disease.

Special Considerations

• Wilson disease: Presents with Coombs-negative haemolytic anaemia and ALF.
• Autoimmune hepatitis: May rarely present with autoimmune haemolytic anaemia.
• Sickle cell hepatopathy: Acute liver dysfunction in sickle cell crisis, sometimes mimicking ALF.

Acute Decompensation of Cirrhosis

 Key Features

• Background of known chronic liver disease or stigmata of cirrhosis (ascites, spider naevi, splenomegaly).
• Can present acutely with jaundice, coagulopathy, and encephalopathy.

Differentiation

• Pre-existing cirrhosis excludes diagnosis of ALF.
• Imaging and clinical history assist in identifying cirrhosis.

Alcoholic Hepatitis in Cirrhosis

 Key Features

• Common in chronic heavy alcohol users.
• Presents with jaundice, hepatomegaly, and systemic inflammation.

Differentiation

• Chronic liver disease markers usually present.
• Encephalopathy and coagulopathy may occur but within the context of acute-on-chronic liver failure.

Autoimmune Hepatitis

 Key Features

• Can present acutely with fulminant hepatitis.
• May also overlap with systemic autoimmune conditions.

Differentiation

• Positive autoimmune serologies (ANA, ASMA, elevated IgG).
• Liver biopsy (transjugular if coagulopathic) may aid diagnosis.

Pregnancy-Related Conditions

Key Features

• Occur in the third trimester or immediately postpartum.
• AFLP and HELLP may mimic ALF, with multi-organ involvement.

Differentiation

• Look for hypertension, proteinuria, thrombocytopenia, and elevated liver enzymes.
• Confirm pregnancy with β-hCG and assess maternal-fetal well-being.
• Imaging may assist in ruling out vascular causes (e.g., hepatic infarcts).

Multiple Organ Dysfunction Syndrome (MODS) in Sepsis

 Key Features

• Systemic inflammatory response with multiorgan dysfunction, including hepatic involvement.
• Jaundice and coagulopathy may be present.

Differentiation

• Often associated with hypotension, fever, leukocytosis, and an obvious source of infection.
• Elevated lactate and positive cultures support sepsis as primary driver.

Initial Assessment and Triage

• Early recognition and aetiological assessment are vital.
• History and physical examination should identify possible drug, viral, or toxin-related causes.
• All patients should undergo early referral to a transplant centre.
• ICU admission is essential for those with hepatic encephalopathy grade ≥2.

Intensive Care Management

• Neurological monitoring for signs of raised intracranial pressure (ICP); elevated risk with grades 3–4 encephalopathy.
• ICP management strategies include:
  • Head elevation to 30°
  • Minimising external stimuli
  • Tracheal intubation for grades 3–4 encephalopathy to secure the airway.
• Preferred sedatives: Propofol and fentanyl (short-acting).
• Fluid balance: Monitor and optimise using central venous and/or pulmonary arterial catheters.
• Early initiation of renal replacement therapy in renal dysfunction or oliguria.
• Enteral nutrition should be provided if oral intake is not possible.
• Monitor blood glucose hourly and correct hypoglycaemia promptly.
• Electrolyte correction (Na⁺, K⁺, Mg²⁺, phosphate) is essential.
• Proton-pump inhibitors or H2 blockers for gastrointestinal bleed prophylaxis.
• Routine use of lactulose and rifaximin is not recommended in ALF-related encephalopathy.
• Periodic surveillance cultures for infection (blood, urine, sputum); prophylactic antibiotics are not routinely advised.

Disease-Specific Therapies

Paracetamol-Induced ALF

• Acetylcysteine is the cornerstone therapy:
  • Administered regardless of dose or delay in presentation.
  • Effective in restoring glutathione and mitigating hepatic injury.
• Activated charcoal is useful if ingestion occurred within 4 hours.

Non-Paracetamol ALF

• Acetylcysteine may offer benefit in grade 1–2 encephalopathy, improving transplant-free survival.
• Mechanisms include reduced cytokine-mediated injury and enhanced hepatic recovery.

Other Targeted Interventions

• HSV hepatitis: IV acyclovir.
• Amanita phalloides toxicity: Gastric lavage, activated charcoal, IV penicillin G, acetylcysteine; contact toxicology centre.
• Autoimmune hepatitis: Corticosteroids may benefit selected patients, but evidence remains mixed.
• Acute hepatitis B: Consider entecavir or tenofovir.
• HELLP/AFLP: Expedite delivery of fetus.
• Budd-Chiari syndrome: Early anticoagulation, consider angioplasty, TIPS, or transplantation if refractory.
• Wilson’s disease:
  • High mortality without transplantation.
  • Chelation therapy is ineffective in fulminant ALF.
  • Consider plasmapheresis or albumin dialysis as a bridge to transplant.

Liver Transplantation

• All patients with ALF should be evaluated for transplant eligibility.
• UNOS Status 1A criteria include:
  • Age >18, <7 days life expectancy, encephalopathy onset <8 weeks, no pre-existing liver disease, ICU admission, and ≥1 of:
    • Ventilator dependence
    • Renal replacement therapy
    • INR >2.0
• Wilson’s disease presenting with haemolytic anaemia is a transplant emergency.

Contraindications to Transplant

• Severe cardiopulmonary disease
• AIDS
• Active malignancy (extrahepatic or metastatic)
• Brain death or irreversible cerebral injury
• Active substance misuse
• Inadequate social support

Aetiology is the most important determinant of outcome

• Paracetamol overdose, acute hepatitis A, and ischaemic hepatitis are associated with higher spontaneous recovery rates.
• Idiosyncratic drug-induced liver injury (DILI), acute hepatitis B, and indeterminate causes are associated with worse outcomes.
• Wilson's disease presenting as ALF has near-uniform lethality without liver transplantation.

Grade of encephalopathy correlates with prognosis

• Grades 3–4 encephalopathy are associated with a poorer outcome, especially in paracetamol-induced ALF.
• A shorter interval between jaundice onset and encephalopathy (i.e., hyperacute liver failure) may paradoxically predict better survival in non-paracetamol causes.

Biochemical and Clinical Predictors

Factor V level

• In paracetamol ALF: levels >10.5% of normal predict survival.
• In non-paracetamol ALF: levels >22% of normal are predictive of survival.
  
  

King’s College Criteria

Paracetamol ALF poor prognostic indicators

• Arterial pH <7.3 or
• PT >100 seconds and serum creatinine >300 µmol/L (3.4 mg/dL) with grade 3–4 encephalopathy.

Non-paracetamol ALF poor prognostic indicators

• PT >100 seconds and any three of the following:
  • Age <10 or >40 years
  • Aetiology: non-A–E viral, halothane, or idiosyncratic DILI
  • Jaundice for >7 days before encephalopathy
  • PT >50 seconds
  • Serum bilirubin >300 µmol/L (17.5 mg/dL)
• Arterial lactate, low pH, and progressively rising PT may also indicate poor prognosis.

Aetiology-Specific Outcomes

Paracetamol overdose

• ~70% spontaneous recovery without liver transplant.
• Rapid progression and biochemical markers aid decision-making.

Wilson’s disease

• Fulminant presentation has a near-100% fatality rate without transplant.
• Associated with Coombs-negative haemolytic anaemia and rapid deterioration.

Autoimmune hepatitis

• Prognosis is variable; corticosteroids may be beneficial in selected cases.
• Advanced liver failure and high MELD scores are associated with poorer outcomes.

Herbal and dietary supplements

• Worse transplant-free survival compared to prescription drug-induced ALF.
• Delay in seeking care contributes to poor outcomes.

Viral hepatitis

• Hepatitis A carries ~50–60% survival in fulminant cases.
• Other viral aetiologies (e.g., hepatitis B, E) carry a poorer prognosis.

Outcomes Following Liver Transplantation

• Liver transplantation dramatically improves survival:
  • 1-year post-transplant survival has improved due to better selection and management.
  • 5-year survival for ALF transplant recipients is approximately 93%.
• Postoperative mortality remains higher than in elective transplantation.
• Preoperative factors such as low arterial pH and BMI are associated with worse outcomes.

Historical Perspective

• Prior to orthotopic liver transplantation, ALF mortality exceeded 80%.
• Currently, overall survival is approximately 60–70%, including both spontaneous recovery and transplanted patients.

Cerebral Oedema and Intracranial Hypertension

• Cerebral oedema is a major cause of mortality in ALF and is strongly associated with advanced grades of hepatic encephalopathy.
• Risk rises significantly with encephalopathy progression: ~35% at grade 3, ~75% at grade 4.
• Management strategies:
  • Elevate head of bed to 30° and minimise environmental stimulation.
  • Use intracranial pressure (ICP) monitoring in patients listed for liver transplantation.
  • Employ transcranial Doppler to estimate cerebral perfusion pressure when ICP monitoring is unavailable.
  • Administer IV mannitol or hypertonic saline for ICP ≥25 mmHg sustained >10 minutes; monitor osmolality (<320 mOsm/kg).
  • Short-term hyperventilation (target PaCO₂ 25–30 mmHg) may temporarily reduce ICP.
  • Consider moderate hypothermia, barbiturate coma, or IV indomethacin in refractory cases.
  • Seizures can precipitate increased ICP and should be treated promptly with anticonvulsants.

Coagulopathy and Haemorrhage

• Coagulopathy is a hallmark of ALF, though significant bleeding is uncommon.
• Routine correction of coagulation parameters is not recommended unless bleeding is present or invasive procedures are needed.
• Use of vitamin K may be trialled, especially in suspected deficiency.
• In cases of active bleeding:
  • Administer fresh frozen plasma (FFP), platelets, or cryoprecipitate.
  • Recombinant factor VIIa may be considered but carries thrombotic risk.
• Gastrointestinal bleeding risk is elevated; prophylactic proton-pump inhibitors or H2 antagonists should be used.

Infection

• Infection is common and frequently contributes to mortality.
• Bacterial infections occur in >80%; fungal infections in up to 30%.
• Surveillance cultures (blood, urine, sputum) should be regularly performed.
• Prophylactic antibiotics are not routinely recommended.
• Initiate empirical antimicrobials if:
  • Progression to grade 3–4 encephalopathy
  • Signs of systemic inflammatory response syndrome (SIRS)
  • Positive cultures or refractory hypotension
  • Patient is listed for liver transplantation
• First-line options: piperacillin/tazobactam and fluconazole; add vancomycin for suspected line-related infections.

Renal Dysfunction

• Acute kidney injury is prevalent, particularly in paracetamol-induced ALF.
• Causes include:
  • Hypovolaemia
  • Acute tubular necrosis
  • Hepatorenal syndrome
• Renal failure is associated with high mortality, especially with creatinine >300 µmol/L.
• Management:
  • Avoid nephrotoxins and NSAIDs.
  • Initiate continuous renal replacement therapy (CRRT) (e.g. CVVHD) over intermittent dialysis to minimise haemodynamic instability and ICP fluctuations.
  • Use noradrenaline or dopamine for vasopressor support if needed.

Metabolic Imbalances

• Hypoglycaemia is frequent due to impaired gluconeogenesis and glycogen depletion.
• Maintain serum glucose at 7.8 mmol/L (140 mg/dL) using continuous IV dextrose infusions (10–20%).
• Hyponatraemia should be corrected cautiously to a target of 140–145 mmol/L to reduce risk of cerebral oedema.
• Other common abnormalities:
  • Hypophosphataemia, hypomagnesaemia, and hypokalaemia – all require aggressive correction.
• Acid–base disturbances (metabolic acidosis or alkalosis) should be addressed based on aetiology.

Seizures

• May result from cerebral oedema or directly from the pathophysiology of ALF.
• Seizures can elevate ICP and compromise cerebral perfusion.
• Use phenytoin for seizure control; benzodiazepines should be minimised due to hepatic clearance issues.

Gastrointestinal Bleeding

• Risk is increased due to stress, coagulopathy, and mechanical ventilation.
• Bleeding sources may include varices, stress gastritis, or portal hypertensive gastropathy.
• INR >1.5 is not a reliable predictor of bleeding risk.
• Prophylaxis with proton-pump inhibitors or H2 blockers is standard.

• Acharya SK, Dasarathy S, Kumer TL, et al. Fulminant hepatitis in a tropical population: clinical course, cause, and early predictors of outcome. Hepatology. 1996;23(6):1448-1455.
• Bernal W, Auzinger G, Dhawan A, Wendon J. Acute liver failure. Lancet. 2010;376(9736):190-201
•  Bernal W, Wendon J. Acute liver failure. N Engl J Med. 2013;369(26):2525-2534.
• Bhatia V, Acharya SK. Predictive value of arterial ammonia for intracranial hypertension in acute liver failure. Gut. 2006;55(3):441-445.
• Bhatia V, Singh R. Acharya SK. Cerebral oedema in acute liver failure in children: profile and outcome. J Gastroenterol Hepatol. 2004;19(3):289-293.\
• Björnsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology. 2005;42(2):481-489.
• Butterworth RF. Pathophysiology of hepatic encephalopathy: a new look at ammonia. Metab Brain Dis. 2002;17(4):221-227.
• Chalasani NP, Hayashi PH, Bonkovsky HL, et al. ACG Clinical Guideline: The diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014;109(7):950-966.
• Chauhan A, Webb G, Ferguson J. Clinical presentations of Hepatitis E: A clinical review with representative case histories. Clin Res Hepatol Gastroenterol. 2019;43(6):649-657.
• Dara L, Liu ZX, Kaplowitz N. Mechanisms of adaptation and progression in idiosyncratic drug-induced liver injury, clinical implications. Liver Int. 2016;36(2):158-165.
• Fujiwara K, Yokosuka O. Acute liver failure in Japan: definition, classification, and prediction of the outcome. J Gastroenterol. 2011;46(Suppl 1):79-86
•  Hirode G, Vittinghoff E, Wong RJ. Increasing Burden of Hepatic Encephalopathy Among Hospitalized Adults. Dig Dis Sci. 2019;64(6):1448-1457.
• Hoyer DP, Paul A, Gallinat A, et al. Donor Risk Index and recipient survival after liver transplantation. Liver Int. 2015;35(5):1617-1626
•  Ichai P, Samuel D. Etiology and prognosis of fulminant hepatitis in adults. Liver Transpl. 2008;14(Suppl 2):S67-S79.
• James LP, Letzig LG, Simpson PM, et al. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab Dispos. 2009;37(8):1779-1784.
• Jaeschke H, McGill MR, Ramachandran A. Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. Drug Metab Rev. 2012;44(1):88-106.
• Jalan R, Williams R. Acute liver failure: pathophysiological basis of therapeutic options. Blood Purif. 2002;20(3):252-261.
• Khuroo MS, Kamili S. Aetiology, clinical course and outcome of sporadic acute viral hepatitis in pregnancy. J Viral Hepat. 2003;10(1):61-69
•  Korman JD, Volenberg I, Balko J, et al. Screening for Wilson disease in acute liver failure: A comparison of currently available diagnostic tests. Hepatology. 2008;48(4):1167-1174.
• Kortsalioudaki C, Taylor RM, Cheeseman P, et al. Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure. Liver Transpl. 2008;14(1):25-30.
• Larsen FS, Schmidt LE. MELD score as a predictor of outcome in patients with acetaminophen-induced liver failure. Hepatology. 2007;45(3):789–796.
• Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: Results of a United States multicentre, prospective study. Hepatology. 2005;42(6):1364-1372
•  Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003;349(5):474-485
•  Lee WM. Etiologies of acute liver failure. Semin Liver Dis. 2008;28(2):142-152.
• Lee WM, Larson AM, Stravitz RT. AASLD guidelines for the management of acute liver failure. Hepatology. 2011;55(3):965-967.
• Lee WM, Stravitz RT, Larson AM. AASLD Position Paper: The Management of Acute Liver Failure. Hepatology. 2011;55(3):965-967
•  Lima LCD, Miranda AS, Ferreira RN, et al. Hepatic encephalopathy: Lessons from preclinical studies. World J Hepatol. 2019;11(2):173-185.
•  O’Grady JG. Acute liver failure. Postgrad Med J. 2005;81(953):148-154.
• O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet. 1993;342(8866):273–275.
• Oketani M, Kawakami H, Arakura N, et al. Efficacy of corticosteroid therapy in patients with acute liver failure due to autoimmune hepatitis. World J Gastroenterol. 2012;18(44):6281-6287.
   Organ Procurement and Transplantation Network. 2021 Annual Data Report.
• Ostapowicz G, Fontana RJ, Schiødt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centres in the United States. Ann Intern Med. 2002;137(12):947-954.
• Plaa GL, Hewitt WR. Detection and evaluation of chemically induced liver injury. Drug Metab Rev. 1982;13(4):487-495.
   Polson J, Lee WM. AASLD Position Paper: Management of Acute Liver Failure. Hepatology. 2005;41(5):1179-1197.
• Ramachandran A, Jaeschke H. Acetaminophen Hepatotoxicity. Semin Liver Dis. 2019;39(2):221-234.
• Reuben A, Koch DG, Lee WM. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52(6):2065-2076.
• Schiødt FV, Bondesen S, Tygstrup N. Predictive value of actin-free Gc-globulin in acetaminophen poisoning. Hepatology. 2001;33(5):1113-1117.
• Schiødt FV, Ostapowicz G, Murray N, et al. Alpha-fetoprotein and prognosis in acute liver failure. Liver Transpl. 2006;12(12):1776-1781.
• Squires RH Jr, Shneider BL, Bucuvalas J, et al. Acute liver failure in children: the first 348 patients in the Pediatric Acute Liver Failure Study Group. J Pediatr. 2006;148(5):652-658.
• Stravitz RT, Kramer AH, Davern T, et al. Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group. Crit Care Med. 2007;35(11):2498-2508.
• Stravitz RT, Lee WM. Acute liver failure. Lancet. 2019;394(10201):869-881.
• Sundaram V, Jalan R, Wu T, et al. Factors Associated with Survival of Patients With Severe Acute-On-Chronic Liver Failure Before and After Liver Transplantation. Gastroenterology. 2019;156(5):1381-1391.e3
•  Sundaram V, Shneider BL, Dhawan A, et al. King's College Hospital Criteria for Non–Acetaminophen–Induced Acute Liver Failure in Children: A Multicenter Assessment. Hepatology. 2021;74(3):1500-1510.
• Teschke R, Schwarzenboeck A, Akinci A. Herbal hepatotoxicity: a critical review. Br J Clin Pharmacol. 2014;77(6):953-971.
• Trey C, Davidson CS. The management of fulminant hepatic failure. Prog Liver Dis. 1970;3:282-298.
• Vento S, Garofano T, Renzini C, et al. Fulminant hepatitis associated with hepatitis C virus superinfection in patients with chronic hepatitis B. N Engl J Med. 1996;334(10):611-615.
• Wendon J, Cordoba J, Dhawan A, et al. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66(5):1047-1081.