Acute Liver Failure (ALF)

Faisal Abaalkhail, M.B.Ch.B, FACP, FRCPC

Consultant Gastroentrology and Transplant Hepatology
Adjunct Professor of Medicine, Al–Faisal University
 Definition and clinical course of ALF
• ALF : acute deterioration of liver function without underlying chronic liver disease

SEVERE ACUTE LIVER INJURY (ALI)

• No underlying chronic liver disease*
• Liver damage
Up to 12 weeks post-jaundice,
(serum aminotransferases 23x ULN)
• Impaired liver function depending on sub-classification
(jaundice and coagulopathy)

HEPATIC ENCEPHALOPATHY (HE)

Crucial for the diagnosis of ALF
Mental alterations may be initially subtle
Intensive screening at the first sign of HE
is mandatory

ALF
*Patients with an acute presentation of chronic autoimmune hepatitis, Wilson disease and Budd–Chiari syndrome are considered as having ALF if they develop hepatic encephalopathy,
despite the presence of a pre-existing liver disease in the context of appropriate abnormalities in liver blood tests and coagulation profile;

EASL CPG ALF. J Hepatol 2017;66:1047–81

 Sub-classifications of ALF
Weeks from development of jaundice to development of HE1
>28 weeks =
chronic liver
0 1 4 12 disease

Hyperacute1 Acute1 Subacute1

+++ ++ + Severity of coagulopathy2

+ ++ +++ Severity of jaundice2

Degree of intracranial
++ ++ +/- hypertension2
Chance of spontaneous
Good Moderate Poor
recovery2
Paracetamol
HBV Non-paracetamol drug-induced Typical cause2
HAV, HEV

+++ High severity; ++ Medium severity; + Low severity; +/- Present or absent

1. O'Grady JG, et al. Lancet 1993;342:2735; 2. Bernal W, et al. Lancet 2010;376:190201;

EASL CPG ALF. J Hepatol 2017;66:1047–81
 Principal aetiologies of ALF
Viral
Hepatitis B, A, E
(less frequent CMV,
Drugs HSV, VZV, Dengue)
Paracetamol, anti-tuberculous, Toxins
chemotherapy, statins, NSAIDs, Amanita phalloides,
phenytoin, carbamazepine, ecstasy, phosphorus
flucloxacillin

ALF

Vascular Other
Budd–Chiari syndrome, Wilson disease, autoimmune,
hypoxic hepatitis lymphoma, malignancy, HLH
Pregnancy
Pre-eclamptic liver rupture,
HELLP, fatty liver of pregnancy

EASL CPG ALF. J Hepatol 2017;66:1047–81

 Assessment and management at presentation
• Immediate measures
• Exclude cirrhosis, alcohol-induced liver injury or malignant infiltration
• Initiate early discussions with tertiary liver/transplant centre
• Even if not immediately relevant
• Screen intensively for hepatic encephalopathy
• Determine aetiology
• To guide treatment and determine prognosis
• Assess suitability for liver transplant
• Contraindications should not preclude transfer to tertiary liver/transplant centre
• Transfer to a specialized unit early
• If the patient has an INR >1.5 and onset of hepatic encephalopathy or other poor prognostic features

EASL CPG ALF. J Hepatol 2017;66:1047–81

 Assessment and management at presentation
• Immediate measures
• Determine aetiology to guide treatment, especially LTx

Primary or secondary causes of ALF and need for transplantation

Disease group Hepatic/primary ALF Extrahepatic/secondary liver
failure and ACLF
Acute liver failure Drug related Hypoxic hepatitis (aka ischaemic)
Acute viral hepatitis Systemic diseases:
Toxin-induced ALF • Haemophagocytic syndromes
Budd–Chiari syndrome • Metabolic disease
Autoimmune • Infiltrative disease
Pregnancy related • Lymphoma
• Infections (e.g. malaria)

CLD presenting with a Fulminant presentation of Wilson disease Liver resection for either secondary deposits or
phenotype of ALF Autoimmune liver disease primary liver cancer
Budd–Chiari Alcoholic hepatitis
HBV reactivation

Possible indication for emergency LTx No indication for emergency LTx

EASL CPG ALF. J Hepatol 2017;66:1047–81

 Differential diagnosis based on clinical features
Aetiology Clinical features
Paracetamol Very high levels of aminotransferases and low level of bilirubin. Rapidly progressive disease, acidosis and renal
impairment. Low phosphate may be seen as a good prognostic marker but replacement is required

Non-paracetamol Subacute clinical course can mimic cirrhosis, clinically and radiographically
Acute Budd–Chiari Abdominal pain, ascites and hepatomegaly; loss of hepatic venous signal and reverse flow in portal vein
syndrome on ultrasound
Wilson disease Young patient with Coombs (DAT)-negative haemolytic anaemia with a high bilirubin to ALP ratio;
Kayser–Fleischer ring; low serum uric acid level; markedly increased urinary copper

Mushroom poisoning
Autoimmune
Malignant infiltration
Acute ischaemic injury
Severe gastrointestinal symptoms after ingestion; development of early AKI
Usually subacute presentation – may have positive autoantibodies, elevated globulin and characteristic lymphocyte
pattern when compared to viral and seronegative aetiologies
History of cancer, massive hepatomegaly; elevated ALP or other tumour markers
Marked elevation of aminotransferases, increased lactic dehydrogenase and creatinine, which normalize soon after
stabilization of haemodynamic instability. Patients with severe congestive heart disease or
respiratory disease

Possible indication for emergency LTx No indication for emergency LTx

EASL CPG ALF. J Hepatol 2017;66:1047–81

 Aetiologies with possible indication for LTx
• Drug-induced liver injury is the most frequent cause of severe ALI and ALF
• Especially paracetamol overdose

At admission, a toxicology screen and determination of paracetamol level are necessary in every patient, although
levels will frequently be negative. If the patient already has coagulopathy and increased serum aminotransferases, N-acetyl
cysteine therapy should be given

Prognosis is worse in patients with staggered ingestion of paracetamol. These cases are more likely to develop
multiple organ failure when compared to those with a single ingestion point

ALF caused by non-paracetamol drug-induced hepatotoxicity is a diagnosis of exclusion

EASL CPG ALF. J Hepatol 2017;66:1047–81

 Aetiologies with possible indication for LTx
• Viral and autoimmune ALF
• HBV (most common), HAV, HEV, and VZV, HSV-1 and -2 (rare) can cause ALF
• Existence of other autoimmune conditions should raise suspicion of autoimmune hepatitis

Always screen for viral aetiologies

Suspect autoimmune aetiology in patients presenting other autoimmune disorders.

Liver biopsy may be needed if elevated globulin fraction and autoantibodies are absent.
Early treatment with steroids may be effective but list for emergency LTx if no improvement within 7 days

EASL CPG ALF. J Hepatol 2017;66:1047–81

 Aetiologies with possible indication for LTx
• Uncommon aetiologies

Assessment of the clinical context is crucial to identify less common causes of ALF

Acute Budd–Chiari syndrome should be suspected in ALF presenting with gross ascites. Diagnosis is based on imaging
techniques

Wilson disease should be suspected with Coombs-negative haemolytic anaemia and high bilirubin to ALP ratio

In cases of HELLP and AFLP in pregnancy, the treatment of choice is prompt delivery of the baby, especially in case of
elevated lactate levels and hepatic encephalopathy. Screening for putative fatty acid defects should be offered

Screen for systemic diseases presenting as ALF

EASL CPG ALF. J Hepatol 2017;66:1047–81

 General support outside ICU
Laboratory analyses at admission

Assess disease severity Check aetiology Test for complications

• PT, INR or factor V and full coagulation • Toxicology screen in urine and • Lipase or amylase
screen paracetamol serum level
• Liver blood tests* • Viral serological screen
• Renal function – HBsAg, anti-HBc IgM (HBV DNA),
– Urine output: hourly HDV if positive for HBV

– Urea† – anti HAV IgM

– Creatinine may be difficult to assay – anti-HEV IgM

in the context of elevated bilirubin – anti-HSV IgM, anti-VZV IgM,
• Arterial blood gas and lactate CMV, HSV, EBV, parvovirus and
VZV PCR
• Arterial ammonia
• Autoimmune markers‡

*Including LDH, conjugated and unconjugated bilirubin and creatinine kinase;

†
Low urea is a marker of severe liver dysfunction;
‡
ANAs, ASMA, anti-soluble liver antigen, globulin profile, ANCAs, HLA typing
EASL CPG ALF. J Hepatol 2017;66:1047–81
 General support outside ICU
Diagnosis, monitoring and care at admission

Diagnostic tests Routine monitoring Standard care Preventative measures

• Cultures (respiratory, blood,
urine)
• Chest X-ray/ECG/liver
echography: axial imaging of
the abdomen and chest may
also be required
• ECG
• Oxygen saturation, blood
pressure, heart rate,
respiratory rate, hourly urine
output
• Clinical neurological status
• Glucose infusions • Avoid sedatives
(10–20%)* • Avoid hepatotoxic and
• Stress ulcer prophylaxis nephrotoxic drugs
• Restrict clotting factors unless
active bleeding
• NAC in early stage, even in
non-paracetamol cases

In case of HE
• Transfer to an appropriate level of care (ideally critical care) at the first symptoms of mental alterations
• Quiet surrounding, head of bed >30°C, head in neutral position and intubate, ventilate, and sedate if progression to >3 coma
• Low threshold for empirical start of antibiotics if haemodynamic deterioration and/or increasing encephalopathy with inflammatory
phenotype
• In case of evolving HE, intubation and sedation prior to the transfer
• Ensure volume replete and normalize biochemical variables (Na, Mg, PO4, K)

*Glycaemic target ± 140 mg/dl, Na 135–145 mmol/l;

EASL CPG ALF. J Hepatol 2017;66:1047–81
 Organ-specific management
Main organ-specific complications in ALF

Coagulation/haemostasis Neurological = cerebral oedema Cranial hypertension

Unbalanced haemostasis Brain death

Thrombocytopenia

Infection Acute liver failure Metabolic

Bacterial, fungal Hypoglycaemia

Pneumopathy Hyponatraemia
Septicaemia Hypophosphataemia
Urinary infection Hypokalaemia

Haemodynamic Pulmonary Renal

Hyperkinetic syndrome Pneumopathy Toxic

Arrhythmia Acute respiratory distress syndrome Functional
Pulmonary overload

EASL CPG ALF. J Hepatol 2017;66:1047–81

Drug Induced Liver Injury
(DILI)
Faisal Abaalkhail, M.B.Ch.B, FACP, FRCPC
Consultant Gastroentrology and Transplant Hepatology
Adjunct Professor of Medicine, Al–Faisal University
 Idiosyncratic DILI: a complex drug–host interaction 1
Drug Drug
Drug

Cellular injuryCellular injury initiation

Cellular
initiation injury initiation
Pharmacological responses
Pharmacological Pharmacological
responses
Reactive responses
metabolites, drug elimination
Reactive metabolites, drug elimination
Reactive metabolites, drugToxicological
eliminationresponses

Toxicological Toxicological responses

responses
Covalent binding, haptenization,
oxidative stress,Covalent
mitochondrial injury, ER stress
Drug properties binding, haptenization, Host factors
properties Covalent binding, haptenization,
Drug properties oxidative Cell
stress, Hosthost
mitochondrial injury, ER stress Possible
death factors
factors
oxidative stress, mitochondrial
Physicochemical injury,
Apoptosis, ER stress
necrosis, DAMP release Genetic variants
Pharmacological
Physiochemical Cell death Race/ethnicity Genetic variants
iochemical Toxicological
Pharmacological Cell death Apoptosis, necrosis, DAMP release Genetic
Age variants Race/ethnicity
macological ToxicologicalApoptosis, necrosis, DAMP release Race/ethnicity
Gender Age
xicological Biophysical effects
Bio-physiological effects Host response to injury insult Age state
Reproductive Gender
iological effects Gender
Nutrition/alcohol/smoking Reproductive state
Immune/inflammation Lifestyles statenutrition, alcohol, smoking
Reproductive
Host response to injury insult Disease conditions Lifestyles
Host response to injury insult nutrition, alcohol, smoking
Medications Disease conditions
Immune/ Lifestyles
Repair Tissue injury Gut flora Medications
Disease conditions
Immune/ inflammation Medications Gut flora
inflammation
Clinical manifestation and outcome Gut flora

1. Chen, et al. J Hepatol 2015;63:503–14. EASL CPG DILI. J Hepatol 2019;70:122261.

 Definition and classification of liver injury
• Serum aminotransferases (ALT/AST), ALP, and TBL levels remain the mainstay for detecting and classifying
liver damage in suspected DILI

General
• DILI should be classified as hepatocellular, cholestatic or mixed according to the pattern of elevation of liver
enzymes based on the first set of laboratory tests available in relation to the clinical event

Aminotransferases
• ALT, ALP and TBL : define liver damage and liver dysfunction in DILI. AST values can reliably substitute ALT in calculating the
pattern of injury when the latter is unavailable at DILI recognition, whereas GGT is less reliable as an ALP substitute

EASL CPG DILI. J Hepatol 2019;70:122261.

 Diagnosis of DILI relies largely on exclusion of alternative causes of
liver damage
Laboratory work-up
• Tests for HCV-RNA and ant-HEV IgM (or HEV-RNA) are suggested in patients with suspected DILI to
exclude acute hepatitis C and/or E, particularly in those cases not compatible with the drug signature of
the suspected causative agent and/or with high transaminase levels
Imaging
• An abdominal ultrasound should be undertaken in all patients suspected of DILI. The use of additional
imaging studies relies on the clinical context
Liver biopsy
• Liver biopsy may be considered during the investigation of selected patients suspected to suffer DILI, as liver
histology can provide information that can support the diagnosis of DILI or an alternative diagnosis

• Liver biopsy may be performed in patients suspected to have DILI when serology raises the possibility
of AIH
• Liver biopsy may be considered in patients when suspected DILI progresses or fails to resolve on withdrawal of the
causal agent as the liver histology may provide prognostic information assisting clinical management

EASL CPG DILI. J Hepatol 2019;70:122261.

Diagnosis: a stepwise approach
Abnormal biochemistry/acute hepatitis

DILI suspicion
Features supporting toxic aetiology
Skin involvement, kidney injury, previous DILI episodes

Careful enquiry of exposure to HDS, drugs, OTC drugs*

Potential pitfalls Discontinue non-essential drugs/HDS treatment

Lack of information (eg. dose, duration), several medications,
hidden HDS and OTC drug intake Search in hepatotoxicity resources (Liver tox)

Calculate biochemical pattern of liver injury

𝐀𝐋𝐓 / 𝐔𝐋𝐍 Hepatocellular Mixed Cholestatic

(𝐑 )
𝐀𝐋𝐏 / 𝐔𝐋𝐍 R≥5 2>R<5 ≤2

*record start and stop dates;

†
hepatic vascular disease, chronic hepatitis,
fibrosis, microvesicular steatosis
EASL CPG DILI. J Hepatol 2019;70:122261.
 Diagnosis: a stepwise approach Abnormal biochemistry/acute hepatitis

DILI suspicion
Features supporting toxic aetiology
Skin involvement, kidney injury, previous DILI episodes

Careful enquiry of exposure to HDS, drugs, OTC drugs*

Potential pitfalls Discontinue non-essential drugs/HDS treatment

Lack of information (eg. dose, duration), several medications,
hidden HDS and OTC drug intake Search in hepatotoxicity resources (Liver tox)

Calculate biochemical pattern of liver injury

𝐀𝐋𝐓 / 𝐔𝐋𝐍 Hepatocellular Mixed Cholestatic

(𝐑 )
𝐀𝐋𝐏 / 𝐔𝐋𝐍 R≥5 2>R<5 ≤2

Search for alternative causes

*record start and stop dates;

†
hepatic vascular disease, chronic hepatitis,
fibrosis, microvesicular steatosis
EASL CPG DILI. J Hepatol 2019;70:122261.
 Diagnosis: a stepwise approach Abnormal biochemistry/acute hepatitis

DILI suspicion
Features supporting toxic aetiology
Skin involvement, kidney injury, previous DILI episodes

Careful enquiry of exposure to HDS, drugs, OTC drugs*

Potential pitfalls Discontinue non-essential drugs/HDS treatment

Lack of information (eg. dose, duration), several medications,
hidden HDS and OTC drug intake Search in hepatotoxicity resources (Liver tox)

Calculate biochemical pattern of liver injury

𝐀𝐋𝐓 / 𝐔𝐋𝐍 Hepatocellular Mixed Cholestatic

(𝐑 )
𝐀𝐋𝐏 / 𝐔𝐋𝐍 R≥5 2>R<5 ≤2

Search for alternative causes

• Viral infections (HAV, HBV, HCV, HEV, EBV, CMV)
• Alcohol-related liver disease, hepatic ischaemia
• Autoantibody titres, ↑ IgG

*record start and stop dates;

†
hepatic vascular disease, chronic hepatitis,
fibrosis, microvesicular steatosis
EASL CPG DILI. J Hepatol 2019;70:122261.
 Diagnosis: a stepwise approach Abnormal biochemistry/acute hepatitis

DILI suspicion
Features supporting toxic aetiology
Skin involvement, kidney injury, previous DILI episodes

Careful enquiry of exposure to HDS, drugs, OTC drugs*

Potential pitfalls Discontinue non-essential drugs/HDS treatment

Lack of information (eg. dose, duration), several medications,
hidden HDS and OTC drug intake Search in hepatotoxicity resources (Liver tox)

Calculate biochemical pattern of liver injury

𝐀𝐋𝐓 / 𝐔𝐋𝐍 Hepatocellular Mixed Cholestatic

(𝐑 )
𝐀𝐋𝐏 / 𝐔𝐋𝐍 R≥5 2>R<5 ≤2

Search for alternative causes

• Viral infections (HAV, HBV, HCV, HEV, EBV, CMV) • Benign/malignant biliary obstruction
• Alcohol-related liver disease, hepatic ischaemia • Primary biliary cholangitis
• Autoantibody titres, ↑ IgG • Primary sclerosing cholangitis

*record start and stop dates;

†
hepatic vascular disease, chronic hepatitis,
fibrosis, microvesicular steatosis
EASL CPG DILI. J Hepatol 2019;70:122261.
 Diagnosis: a stepwise approach
Abnormal biochemistry/acute hepatitis

DILI suspicion
Features supporting toxic aetiology
Skin involvement, kidney injury, previous DILI episodes

Careful enquiry of exposure to HDS, drugs, OTC drugs*

Potential pitfalls Discontinue non-essential drugs/HDS treatment

Lack of information (eg. dose, duration), several medications,
hidden HDS and OTC drug intake Search in hepatotoxicity resources (Liver tox)

Calculate biochemical pattern of liver injury

𝐀𝐋𝐓 / 𝐔𝐋𝐍 Hepatocellular Mixed Cholestatic

(𝐑 )
𝐀𝐋𝐏 / 𝐔𝐋𝐍 R≥5 2>R<5 ≤2

Search for alternative causes

• Viral infections (HAV, HBV, HCV, HEV, EBV, CMV) • Benign/malignant biliary obstruction
• Alcohol-related liver disease, hepatic ischaemia • Primary biliary cholangitis
• Autoantibody titres, ↑ IgG • Primary sclerosing cholangitis

Consider liver biopsy if

• Negative or incomplete rechallenge
*record start and stop dates; • Acute or chronic atypical presentation †
†
hepatic vascular disease, chronic hepatitis,
fibrosis, microvesicular steatosis • Autoimmune hepatitis
EASL CPG DILI. J Hepatol 2019;70:122261.
 Therapy
• Most important initial step in terms of management of suspected DILI is to discontinue the implicated
agent

Specific therapies
• Cholestyramine: a short administration may be used to decrease the course of
hepatotoxicity induced by very selected drugs, such as leflunomide and terbinafine
• Carnitine may be used to decrease the course of valproate hepatotoxicity
• The efficacy of NAC to improve the severity of liver injury from drugs other than paracetamol
may not be significantly substantiated
• The efficacy of UDCA to reduce the severity of liver injury may not be significantly
substantiated

EASL CPG DILI. J Hepatol 2019;70:122261.