This document provides information about acute liver failure (ALF), including its definition, etiology, pathophysiology, clinical features, investigations, prognosis, and management. ALF is characterized by severe liver injury and encephalopathy within 8 weeks without pre-existing liver disease. Common causes include drugs/toxins, viral hepatitis, and autoimmune conditions. In ALF, liver cells die rapidly, impairing ammonia clearance and coagulation factor production, which can lead to cerebral edema, coagulopathy, and multi-organ failure without transplantation. Prognosis is assessed using tools like KCH or ALFED scores. Management involves supportive care, treating the underlying cause, and considering transplantation for eligible patients.

1. ACUTE LIVER FAILURE
DR. VIJAY YADAV
MD. INTERNAL MEDICINE
LECTURER, NMCTH

2. FUNCTIONS OF LIVER

3. < 28 weeks

4. 5 – 12 weeks

5.  Severe liver injury
 Potentially reversible in nature
 Onset of hepatic encephalopathy within 8
weeks of first symptoms
 In the absence of pre-existing liver disease

6. ETIOLOGY
INDIA
NEPAL
WEST

8. ETIOLOGY
 Acute liver failure:
 Drugs/Toxin
 Acute viral hepatitis
 Autoimmune hepatitis
 Budd-chairi syndrome
 Pregnancy related
 Chronic liver disease
presenting with a
phenotype of ALF:
 Wilson’s disease
 Autoimmune hepatitis
 Budd chairi syndrome
 HBV reactivation
 Ischemic/Hypoxic
hepatitis
 Malignancy:
 Metastatic breast cancer
 Lymphoma
 Infections:
 Malaria
 Dengue
 Rickettsia
 Leptospirosis etc..
Hepatic/Primary ALF
Needs emergency LTx
Extrahepatic/Secondary ALF
Do not need emergency LTx

10. Amino Acids removal-basic concepts
AA α KETOACIDS
THE AMINO GROUP IS PUT
INTO α KETOGLUTARATE TO
GENERATE GLUTAMATE
ALT REMOVES THE AMINO
GROUP FROM GLUTAMATE
& PUTS IT INTO PYRUVATE
TO MAKE ALANINE

11. ALT IN LIVER REMOVES AMINO GROUP FROM
ALANINE & REGENERATES PYRUVATE
THE AMINO GROUP IS PUT BACK TO α
KETOGLUTARATE TO REGENERATE GLUTAMATE
THE NITROGEN OF GLUMATE IS DUMPED TO
UNDERGO UREA CYCLE

13. UREA CYCLE

14. PATHOPHYSIOLOGY
In a normal liver,
the hepatocytes
divide & produce
daughter cells which
replenish the pool
of hepatocytes.
In addition, the
normal hepatocytes
take in ammonia
(NH3) from the
portal circulation &
releases urea.
 In ALF, the hepatocytes dies & NH3
uptake and filtering is impaired.
 This causes release of NH3 into
peripheral circulation which crosses
BBB.
 NH3 is a major neurotoxin that comes
from glutamine metabolism.
 NH3 in the brain causes conversion
of glutamate to glutamine with the
help of glutamine synthetase that
results in astrocyte swelling and
cerebral edema.
 At the same time, inflammatory
cells(kupfer cells & macrophages) are
recruited from the ECM that causes
release of pro-inflammatory cytokines
into the circulation, i.e. histones
which inhibit hepatocyte cell division
& contributes to further liver
dysfunction.

15.  Release of materials from the dying cells & spill-over of
pro-inflammatory mediators from the splanchnic area to
systemic circulation results in CV instability resembling
vasodilatory systemic shock with low BP that results in
decreased CPP.
 This coupled with loss of cerebral autoregulation results in
cerebral hypoperfusion and worsening of cerebral edema.
 ↑PGE2 & Thromboxane that lead to DIC
 Loss of hepatocytes results in loss of synthetic function of
the liver that leads to decrease in clotting factors II, V, VII,
IX, & X along with hypoalbuminemia.
 Hypoglycemia due to impaired gluconeogenesis.

17. ORGAN CLINICAL FEATURES PATHOGENESIS
BRAIN HE, Cerebral Edema, ↑ICP NH3 induced astrocyte swelling,
Hypoglycemia
LUNGS Respiratory failure ARDS, DAD
HEART Hypotension
High output state
Subclinical myocardial injury
Vasodilation, Hypovolemia
BLOOD
LYMPHOCYTES
BONE MARROW
Coagulopathy
Infections & Sepsis
Suppression
↓Clotting factor synthesis
Thrombocytopenia
Fibrinolysis
Reduced/Impaired fxn
Viral & Seronegative disease
GIT UGIB Stress ulceration, Coagulopathy
LIVER Hypoglycemia
Lactic acidosis
Hyperammonemia
Portal HTN
↓Gluconeogenesis
↓Lactate clearance(↓Cori’s cycle)
↓Ammonia clearance
In subacute disease
PANCREAS Pancreatitis Esp in APAP toxicity
ADRENAL GLAND Hypotension ↓Glucocorticoid production
KIDNEY Renal failure Hypovelemia, ATN, HRS

18. CAUSES OF CEREBRAL EDEMA IN ALF
NH3 in the brain causes conversion of glutamate to
glutamine with the help of glutamine synthetase that
results in astrocyte swelling and cerebral edema.
Release of pro-inflammatory cytokines from splanchnic
area to systemic circulation causes widespread
vasodilation and ↓SBP that results in ↓CPP.
This coupled with loss of cerebral autoregulation
results in cerebral hypoperfusion and worsening of
cerebral edema.

19.  Asterixis ,Tremor, Constructional apraxia in grade 1 & 2
 Hyperreflexia, Clonus, Rigidity in grade 3 & 4
GRADE 1 Reversal of sleep awake cycle
Difficulty with concentration
GRADE 2 Drowiness, Disorientation, Confusion
GRADE 3 Stupor
GRADE 4 Coma

20. COAGULATION DEFECTS IN ALF
Decreased Normal Increased
↓Platelet: ↑destruction of platelet & ↓thrombopoietin
production
Factor V level: Most sensitive test to monitor liver recovery
as it has the shortest half life of all.
Platelets
Fibrinogen
Factors
5,7,9,10,11,13
Plasminogen
α2 Antiplasmin
D-dimer
PT
aPTT
TT
Factor 8
vWF
FDP
Plasmin

21.  Fibrin & Fibrinogen
degradation product
(FDP) are protein
fragments resulting from
action of plasmin on fibrin
or fibrinogen.
 Elevated levels are seen
in states of fibrinolysis,
e.g. DIC
 FDP assays do not
differentiate between
fibrin degradation
products & fibrinogen
degradation prodcut.
 Indicates bleeding
tendency
 It is possible to
accurately measure the
concentration of
degradation products
of cross – linked fibrin
known as D – dimer.
 Indicates thrombotic
tendency
FDP D - dimer

22. INVESTIGATIONS
Complete Blood Counts (CBC) & PBS
Renal Function Tests
Liver Function Tests + PT/INR
PT is the best predictor of prognosis in acute hepatocellular
injury.
PT > 4 sec above normal = ↑risk of hepatic failure
Blood glucose & Electrolytes
Blood grouping & cross matching
Serum APAP levels
ABG + Serum lactate
Arterial Ammonia levels
• <75 μg/dL: rarely a/w encephalopathy
• >123 μmol/L: adverse outcome
• >150 μmol/L: a/w cerebral edema
• >200 μg/dL: a/w cerebral herniation
Hyperammonemia
Other causes???

23. INVESTIGATIONS
CONT..
Viral hepatitis serologies
Autoimmune markers: ANA, ASMA etc…
Serum ceruloplasmin, 24 hour urinary copper
Pregnancy test if female
Toxicology screen of blood & urine
USG of liver & Doppler of hepatic veins
Transjugular liver biopsy : Wilson’s, AH, Malignancy
Percutaneous liver biopsy is contraindicated d/t
coagulopathy.
Type 1 AH: ANA, ASMA
Type 2 AH: Anti-LKM 1, Anti-liver
cytosol 1
Type 3 AH: Anti-SLA

24. Prognosis
King’s College Hospital Criteria (KCH)
ACETAMINOPHEN ALF NON-ACETAMINOPHEN ALF
• Arterial pH < 7.3 or
• Arterial lactate > 3.5mmol/L
at 4 hour or
• Arterial lactate > 3.0mmol/L
at 12 hour or
• INR > 6.5 (PT > 100 sec) &
• Creatinine > 3.4mg/dL &
• Encephalopathy grade 3/4
• INR > 6.5 (PT > 100 sec) or
• Any 3 of the following 5:
▫ Age < 10 or > 40 yr
▫ Bilirubin > 17.5 mg/dL
▫ Cause: Non-A, non-B
hepatitis, halothane
hepatitis, idiosyncratic
drug reactions,
indeterminate
▫ Duration of jaundice > 7
days
▫ INR > 3.5 (PT > 50 sec)

25. Acute Liver Failure Early Dynamic
(ALFED) score
Predictors of
mortality
Score on admission Score on Day 3
HE grade ≥ 2 1 2
INR ≥ 5 1 1
Arterial ammonia
≥123μmol/L
1 2
Bilirubin ≥ 15mg/dL 1 1
Low risk: Score 0-1; Mortality 0-5.6%
Moderate risk: Score 2-3; Mortality 19-21%
High risk: Score 4; Mortality 67%,
Score 5; Mortality 84%
Score 6; Mortality 100%

26. MANAGEMENT OF ALF
GENERAL

27. Nutrition
• Hepatic glucose metabolism like glycogen storage and
gluconeogenesis are disordered
• High energy requirement
• Fat & muscle stores are depleted
• Caloric requirement: 50kcal/kg/day
• Protein: 1g/kg/day
• Enteral nutrition preferred to parenteral

28. APAP INDUCED ALF
 Activated charcol < 1-2 hours
 Give NAC within 24 of
ingestion; however mortality
benefit if given < 8 hours
 Intravenous:
 150mg/kg over 1 hour f/b
 12.5mg/kg over next 4 hours
 then 6.25mg/kg/hr for 67 hours
 until serum APAP is measurable
and improvement in hepatic
function.
NON- APAP INDUCED ALF
 Effective in stage 1-2 HE
 Same dose as that for
APAP induced ALF
L-Ornithine L- Aspartate (LOLA)
1o gmTDS

29. Cerebral edema/Raised ICP
Grade I/II encephalopathy Grade III/IV encephalopathy
• Transfer to liver transplant
center & list for transplant
• CT brain to r/o other causes of
altered MS
• Avoid stimulation/sedation
• Lactulose: Possibly helpful
• Elevate head end to 30⁰
• Tracheal intubation – Propofol is
the sedative of choice
• ICP monitoring by placement of
ventriculostomy tube.
• Mannitol: 0.5-1g/kg bolus;
repeated if needed & maintain
serum osmolarity < 320mosm/L
• Hypertonic saline: Target Na
145-155 mEq/L
• Hyperventilation to maintain
PaCo2 of 25-35 mmHg
• Hypothermia: 33-34⁰C
• Phenytoin for seizures, no role of
prophylaxis

30. Hemodynamic management
• Hemodynamic derangement common due to low SVR
• Resuscitate with crystalloid ( 0.9% NS)
• Vasopressor support for refractory cases ( MAP < 50 mmHg)
• 1st choice: Noradrenaline
• 2nd choice: Vasopressin
• Goals: MAP = 75 mmHg; CPP = 50 – 60 mmHg
• If refractory to all: IV hydrocortisone

31. COAGULOPATHY
Inj Vitamin K 10mg IV OD for 3 days
Whole Blood:
• 1 unit = 450ml
• For acute massive bleeding
Packed Cell Volume (PCV):
• WBC & Platelets are removed
• 1 unit = 250ml
• 1 unit raises Hct by 3%
Platelet Rich Plasma (PRP):
• 1 unit = 50ml
• Raises platelet by 5000 - 8000
Fresh Frozen Plasma (FFP):
• 1 unit = 250ml
• Factors 2,7,9,10,11,12, & 13
• For emergency reversal of warfarin
Cryoprecipitate:
• 1 unit = 10ml
• Factors 8,13, vWF, and Fibrinogen
No role of
prophylactic blood
products
Stress Ulcer
prophylaxis by IV PPI
or H2 blockers

32. INFECTION SURVEILLANCE & PREVENTION
 M.C sites of infection: respiratory tract, urinary tract, & blood
 Send blood, sputum, and urine cultures
 Controversial role of prophylactic antibiotics
 Give antibiotics if active infection, culture positive, or clinical
deterioration ( progression to high grade HE/evidence of SIRS)
 Antibiotic of choice: Tazobactam/Piperacilline or Fluroquinolones
 Do not disregard fungal infection

33.  Renal Replacement Therapy (RRT)
 Continuous forms (CVVH) are preferred
Renal Failure

34. MANAGEMENT OF ALF
Treatment of
underlying
causes

35. • Acetaminophen toxicity: NAC preferably within 8 hours
• Hepatitis B: Nucleos(t)ide analogue like Entecavir, Tenofovir
• Hepatitis E: Oral Ribavarin 600 -800 mg/d x 28 days (not in pregnancy)
• Mushroom poisoning: Activated charcol; Penicillin G, Silibinin
• Herpes Simplex Virus: IV Acyclovir 5-10mg/kg TDS x 7 days
• Wilson’s disease: Liver Transplantation; no role of chelation therapy
• Autoimmune hepatitis: Prednisolone 40-60mg/d x 2 weeks f/b LT
• Acute fatty liver of pregnancy: No specific medical treatment
• Acute Budd Chairi syndrome: Anticoagulation ± Stenting
• Treat specific infections, e.g. anti-malarials for malaria
• Ischemic hepatitis: Correct hypovolemia

36. COMPLICATIONS OF ALF
 Cerebral edema & HE
 Hypoglycemia
 Metabolic acidosis
 Infection
 Renal failure
 MODS
 Respiratory failure

37. THANK
YOU