Acute Liver Failure
• Acute liver failure describes the clinical syndrome of severe
impairment of liver function Encephalopathy
• Within 6 months of the onset of symptoms.
DEFINITION (PALF study group)
1.The acute onset of liver disease with no known evidence of chronic
2. Biochemical and/or clinical evidence of severe liver dysfunction:
• Hepatic-based coagulopathy – prothrombin time [PT] ≥15 seconds or
international normalized ratio [INR] ≥1.5 that is not corrected by
parenteral vitamin K in presence of clinical hepatic encephalopathy
• PT is ≥20 seconds or INR is ≥2.0 in presence or absence of HE .
• An alternative classification
fulminant and sub-fulminant • liver failure - time from jaundice to encephalopathy less or more than
Late onset liver failure describes encephalopathy developing more
than 8 weeks (but lessthan 24 weeks) after the first symptoms
Acute vs acute on chronic liver failure
Acute liver failure
Acute on chronic liver failure
Hard / increased
Herpes Virus , Hepatitis B virus
Inborn Error of Metabolism
Hereditary Fructose Intolerance , Galactosemia
CHD , Cardiac Surgery , Myocarditis
Hep A , Hep B , Herpes Virus , NANB Hepatis
Valproate , Isoniazide , Paracetamol (Common)
Inborn Error of metabolism
Hereditary Fructose Intolerance
2-18 years old
NANB Hepatitis ,Hep A , Hep B (common)
Same As Infants
Budd Chiari Syndrome
• In India , infectious hepatitis is the most important cause of ALF
• In Infants , main causes are inherited metabolic disorders and
• Massive destruction of hepatocytes – direct cytotoxic effect or
immune response to antigens
• Contributing factors to liver failure – impaired hepatocyte
regeneration , altered parenchymal perfusion , endotoxemia
• The patient, previously having been well, typically develops non-specific
symptoms such as nausea and malaise.
• Progressive Jaundice.
• Vomiting is common
• Abdominal pain .
• Rapid decrease in liver size without clinical improvement is an omnious
• Tachycardia, hypotension, hyperventilation and fever are later features
• Later coma & encephalopathy features
Signs of Liver cell failure
• Progressive Jaundice
• Sweetish, slightly faecal smell of the breath
• Of intestinal origin
• Normal demethylating processes being inhibited by liver damage.
• Methyl mercaptans excreted through lungs
• Frequent in patients with an extensive portal-collateral circulation
• Often precedes coma
Skin changes - Vascular spiders
• Found in the vascular territory of the superior vena cava.
• Common sites are the necklace area,the face, forearms and dorsum
of the hand
• An arterial spider consists of a central arteriole, radiating from which
are numerous small vessels resembling a spider’s legs
• Pressure on the central prominence with a pinhead causes blanching of the
• Disappear with improving hepatic function, whereas the appearance of fresh
spiders is suggestive of progression.
• A few spiders are not sufficient to diagnose liver disease, but many new ones,
with increasing size of old ones, should arouse suspicion.
Palmar erythema (liver palms)
• The hands are warm and the palms bright red in colour,especially the
hypothenar and thenar eminences and pulps of the fingers
• The mottling blanches on pressure and the colour rapidly returns.
• Vascular spiders and palmar erythema - attributed to oestrogen
• Oestrogens have an enlarging, dilating effect on the spiral arterioles
of the endometrium, and such a mechanism may explain the closely
similar cutaneous spiders
• Liver inactivates oestrogen– in liver failure it leads to increase in
oestrogen levels – leads to cutaneous manifestations of liver failure
Endocrine changes - Hypogonadism
• Diminished libido and potency are frequent
• The testes are soft and small. Seminal fluid is abnormal in some cases.
• Secondary sexual hair is lost
• The female has ovulatory failure.
• Loses feminine characteristics, particularly breast and pelvic fat.
• Gynaecomastia - Alcoholic liver disease is the commonest
• Steroid hormones are conjugated in the liver.
• Derivatives of oestrogens, cortisol and testosterone are conjugated as a
glucuronide or sulphate
• So excreted in the bile or urine.
• Failure of hormone metabolism in liver failure results in a rise in blood
• This alters the normal homeostatic balance between secretion rates of
hormones and their utilization.
• The prothrombin time (together with the degree of encephalopathy) refractory to vitamin K treatment central to the assessment of the severity of the clinical situation, and its progress.
• Haemoglobin and white count are obtained.
• A falling platelet count may reflect disseminated intravascular coagulation.
• Blood Glucose
• Blood Urea
• Serum Electrolytes
• Serum Creatinine
• Serum bilirubin
• Serum Albumin – initially normal but later low albumin carries poor
• Transaminases – of little prognostic values as levels tends to fall as
Etiological Work Up
• Virological markers –
IgM Anti HBc
IgM anti HAV
• The Guidelines now used for decision on management no longer
depend on EEG
• Continuous EEG has shown 50% of patients with subclinical seizure
and epileptiform activities
• Recommended for Grade 3 and 4 Encephalopathy
Liver Biopsy & CT Brain
• Hepatic Parenchymal necrosis more than 50% indicates poor prognosis
• Hepatic Regenerative changes on histology (<50% Necrosis ) indicates good
• From Practical point of view – clinical & laboratory data rather than biopsy
are used for decision making
• CT – unreliable in detecting early cerebral oedema so movement of patient
to radiology carries the risk of deterioration
• Volume resuscitation should be carried out aggressively
• Fluids should be glucose based with infusion rate at least 6-8
• Strict input output charting
• The brain is exposed to increased levels of ammonia,
neurotransmitters and their precursors because of failed hepatic
• Neurological and psychiatric components.
• Features of encephalopathy can be separated into changes in
consciousness, personality, intellect and speech.
• Disturbed consciousness with disorder of sleep is usual.
• Hypersomnia appears early and progresses to reversal of the normal
• Reduction of spontaneous movement, a fixed stare, apathy, and
slowness and brevity of response are early signs.
• Further deterioration results in reaction only to intense or noxious
• Coma at first resembles normal sleep, but progresses to complete
Personality & intellect changes
• Irritability and loss of concern for family.
• Intellectual deterioration varies from slight impairment of organic mental function to gross confusion.
• Isolated abnormalities appearing in a setting of clear consciousness relate to disturbances in visual spatial
• Most easily elicited as constructional apraxia, shown by an inability to reproduce simple designs with
blocks or matches
• Writing is oblivious of ruled lines and a daily writing chart is a good check of progress
• Failure to distinguish objects of similar size, shape, function and position
• Micturating and defaecating in inappropriate places
• Speech is slow and slurred and the voice is monotonous.
• The most characteristic neurological abnormality is the ‘flapping’
• This is due to impaired inflow of joint and other afferent information
to the brainstem reticular formation resulting in lapses in posture.
• It is demonstrated with the patient’s arms outstretched and fingers
separated or by hyperextending the wrists with the forearm fixed .
The rapid flexion–extension movements at the metacarpophalangeal
and wrist joints are often accompanied by lateral movements of the
• ‘Flapping’ tremor is not specific for hepatic pre-coma.
• It can also be observed in uraemia, in respiratory failure and in severe heart
• Deep tendon reflexes are usually exaggerated.
• Increased muscle tone is present at some stage and sustained ankle clonus is
often associated with rigidity.
• During coma , patients become flaccid and lose their reflexes.
• The clinical course fluctuates, and frequent observation of the patient is
• Clinical grading should be used as a part of the clinical record
• The basic processes are failure of hepatic clearance of gut derived
substances, either through hepato-cellular failure or shunting, and
altered amino acid metabolism
• Result in changes in cerebral neurotransmission.
• Several neuroactive toxins, in particular ammonia, and
neurotransmitter systems are thought to be involved and inter-relate.
• In patients with poor hepato-cellular function, such as acute hepatitis,
the shunt is through the liver itself.
• The damaged cells are unable to metabolize the contents of the portal
venous blood completely so that they pass unaltered into the hepatic
• In patients with more chronic forms of liver disease the portal blood
bypasses the liver through enlarged natural ‘collaterals’.
• The portal– hepatic vein anastomoses, developing around the damaged
liver, act as shunt.
• Patients going into hepatic coma are suffering from cerebral
intoxication by intestinal contents which have not been metabolized
by the liver - portal-systemic encephalopathy
• Ammonia is produced from the breakdown of proteins,amino acids, purines and
• Ammonia arising from the intestine is synthesized by bacteria, dietary protein and
• The liver normally converts ammonia to urea and glutamine through the urea cycle.
• Liver failure causes disorder of the urea cycle lead to an encephalopathy.
• Blood ammonia levels &Brain levels are also increased
• Increase in the cerebral metabolic rate for ammonia and an increase in the blood–
brain barrier permeability to ammonia
Effects of ammonia on brain
• The primary mechanisms proposed for ammonia in hepatic
encephalopathy - direct effect on neural membranes or on postsynaptic inhibition
• An indirect neuronal dysfunction due to disturbance of glutamate
• No urea cycle in the brain
• Ammonia removal involves a different pathway.
• In astrocytes, glutamine synthetase converts glutamate plus ammonia to glutamine .
• With excess ammonia, glutamate (an important excitatory neurotransmitter) is depleted, and
• Principal inhibitory neurotransmitter
• GABA is synthesized by gut bacteria, and that entering the portal vein
is metabolized by the liver.
• Liver failure or portal-systemic shunting - enters the systemic
• There are increased GABA levels in the plasma of patients with liver
disease and hepatic encephalopathy – neuroinhibition
• Receptor is part of a larger receptor complex which also has binding sites for
benzodiazepines and barbiturates.
• The binding of any of these ligands - opens a chloride channel - hyperpolarization
of postsynaptic membrane - neuroinhibition.
• Endogenous benzodiazepines are present in patients with hepatic
encephalopathy - interact with the receptor complex and cause neuroinhibition.
• No unifying mechanism explains hepatic encephalopathy.
The brain controls neuropsychiatric behaviour through multiple inhibitory and stimulatory
receptor mediated pathways.
• Cerebrospinal fluid - usually clear and under normal pressure , cell
count is normal
• Electroencephalogram(EEG) - bilateral synchronous slowing of the
• EEG changes occur very early even before psychological or
• CT scan to show cerebral oedema and cortical atrophy even in those
with subclinical portal-systemic encephalopathy.
Treatment of Hepatic Encephalopathy
• Treatment broadly divides into three areas.
1 Identification and treatment of the precipitating cause.
2 Intervention to reduce the production and absorptionof gut-derived ammonia
and other toxins.
• Involves reduction and modification of dietary protein,
• Alteration of enteric bacteria and the colonic environment antibiotics,lactulose/lactilol
• Stimulation of colonic emptying - enemas, lactulose/lactilol.
3 Agents to modify neurotransmitter balance directly- bromocriptine, flumazemil limited clinical value at present.
150% of recommended allowance
2-3 g /kg/d
It promotes growth & maintain
positive nitrogen balance
Vegetable Proteins - preferred
Grade 1 & 2 – 1-2 g/kg/d
Grade 3 &4 – 0.5 g /kg/d
Further protein restriction
exacerbate HE by causing
breakdown of endogenous proteins
• Neomycin, given orally, is very effective in decreasing gastrointestinal
ammonium formation - used for the acute case for 5–7 days
• In acute hepatic coma, lactulose is given -- neomycin added if the
response is slow or partial.
• Metronidazole seems to be as effective as neomycin.
• Rifaximin, a non-absorbed derivative of rifamycin, is effective for
grade 1–3 hepatic encephalopathy
Lactulose and lactilol
• Given by mouth lactulose
• Reaches the caecum where it is broken down by bacteria predominantly to lactic acid .
• The faecal pH drops.
• Faecal acidity would reduce the ionization and hence absorption of ammonia
• The growth of lactose-fermenting organisms is favoured and organisms such as bacteroides,
which are ammonia formers, are suppressed.
• The aim of treatment with lactulose is to produce acid stools without diarrhoea.
• The dose is 10–30ml three times a day and is adjusted to produce two semi-soft stools daily.
• The effects of lactilol compared with lactulose
Colonic effects similar
As effective in encephalopathy
More convenient (powder)
Less diarrhoea and flatulence
No longer routinely available
Purgation to prevent constipation - Lactulose or lactose enemas may be used and are superior to
water . All enemas must be neutral or acid to reduce ammonium absorption.
Sodium benzoate and L-ornithine -L-aspartate
• Sodium benzoate promotes urinary excretion of ammonia and is as effective as
lactulose and is less expensive.
• L-ornithine-L-aspartate treatment promotes hepatic removal of ammonia by
stimulating residual hepatic urea cycle activity and promoting glutamine
synthesis, particularly in skeletal muscle
• Flumanezil - benzodiazepine-receptor antagonist which can induce transient, variable but
distinct improvement in some patients with hepatic encephalopathy
• Clinical situation has yet to be established.
• Patients are extremely sensitive to sedatives and whenever possible these are avoided
• Zinc Supplementation – deficiency may reduce metabolism of ammonia to urea because
of the dependency on zinc of some of the enzymes involved
• Studies of zinc therapy in hepatic encephalopathy have not established benefit
Cerebral edema (intracranial hypertension)
• Uncommon in patients with grade 1 or 2 encephalopathy
• Develops in the majority with grade 4.
• Raised intracerebral pressure can lead to brainstem herniation and is
the most common cause of death, being found in 80% of fatal cases
• Two mechanisms have been proposed: cytotoxic and vasogenic.
o The cytotoxic hypothesis - accumulation of osmolytes such as glutamine, in astrocyte subsequent osmotic uptake of water into the cells.
o In the brain astrocytes are the site of ammonia metabolism by amidation of glutamate to
o In acute liver failure cerebral glutamine concentrations rise.
• The vasogenic hypothesis - changes in cerebral blood flow and the blood–brain
• Cerebral blood flow autoregulation (maintained blood flow despite falling or rising
blood pressure) is lost in patients with fulminant hepatic failure .
• Loss of this protective mechanism could exacerbate cerebral changes due to systemic
hypotension (giving cerebral ischaemia) and cerebral hyperperfusion- increasing
cerebral blood volume and interstitial water
• If not controlled - progresses to loss of pupillary reflexes and respiratory arrest from
• Head should be elevated to 30 degrees
• High levels of PEEP should be avoided – it may increase hepatic venous pressure
& intracranial pressure
• Mannitol bolus of 0.5 g/kg as 20 % solution over 15 minutes – can be repeated if
serum osmolality less than 320 mOsm/L
• Other methods 3% hypertonic saline
• STEROIDS ARE NOT INDICATED IN TREATMENT OF INTRACRANIAL HYPERTENSION
in ALF – as it may complicate infection & cause gastric erosions
• The liver synthesizes all the coagulation factors (except factor VIII) inhibitors of coagulation and
proteins involved in the fibrinolytic system.
• The coagulopathy of fulminant hepatic failure is complex
• Not only to factor deficiency, but also to enhanced fibrinolytic activity
• The platelet count may fall due to increased consumption or reduced production, and platelet
function is also abnormal in hepatic failure.
• The resulting coagulopathy predisposes to bleeding- potential cause of death
• The prothrombin time is the most widely used test to assess coagulation. It is a guide to prognosis.
• Iv vitamin K to correct any reversible coagulopathy
• FFP – to be given in case of haemorrhage or if coagulopathy is severe
• Thrombocytopenia to be corrected
• Prophylaxis for GI bleed – administration of PPI , sucralfate , ranitidine
Metabolic , electrolyte and acid base disturbances
• Hypokalemia – decreased dietary intake , chronic illness , secondary hyperaldosteronism , frequent GI
• Hypophosphatemia – due to amount of regenerative liver mass as phosphate be a substrate for
various kinase enzymes that phosphorylate proteins for liver regeneration
• Hypoglycemia – failure of hepatic gluconeogenesis , high plasma insulin levels due to decreased
• Respiratory alkalosis – due to hyperventilation – direct stimulation of respiratory centre by toxic
3 Meq (1.5 ml kcl ) if K+ >3 Meq
4 Meq (2 ml kcl ) if K+ is 2.5 - 3 Meq
5 Meq (2.5 ml kcl ) if K+ is 2 – 2.5 Meq
6 Meq (3 ml kcl ) if K+ is < 2 Meq
Restrict sodium infusion to < 2 Meq
Maintain blood sugar levels between 100 –
• Ninety per cent of patients with acute liver failure and grade 2 or
more encephalopathy have clinical or bacteriological evidence of
• The majority of infections are respiratory.
• The high rate of infection can be related to poor host defences with
impaired Kupffer cell and polymorph function
• Hepatorenal syndrome is the most common cause of renal
insufficiency in ALF
• Secondary to renal vasoconstriction
• Type 1 – rapidly progressive in renal function , doubling of s.
creatinine to a level > 2.5 mg/dl or 50 % reduction in CrCl to < 20
ml/min in less than 2 weeks
• Type 2 – progression slow , > 2 weeks
• Primarily focussed on decreasing splanchic circulation –
1. Vasoconstrictors – Terlipressin
2. Alpha agonist- nor-epinephrine , medodrine
Very effective in reversal of functional renal insufficiency
• Overall survival for those reaching grade 3 or 4 encephalopathy is 20% without
• If only grade 1 or 2 coma is reached, survival is around 65%.
• Aetiology is important - 66% for hepatitis A, 38.9% for hepatitis B and 50% for
• Decerebrate rigidity, with loss of the oculovestibular reflex and respiratory failure
are particularly ominous
• Prothrombin time is the best indicator of survival
• The association of a clotting factor V concentration of less than 15% with coma is
• Liver biopsy -Hepatic parenchymal necrosis of more than 50% is
associated with a reduced survival
• The causes of death are: cerebral oedema, infection, bleeding,
respiratory and circulatory failure, renal failure, hypoglycaemia and
• Hyper-acute liver failure - the chance of survival without
transplantation is more than in acute liver failure
Auxiliary liver transplantation
• The native liver is left in place
• Donor liver graft either placed in the right upper quadrant alongside the native liver
(heterotopic), or part of the native liver is resected and replaced with a reduced size graft
• The intention - to provide viable liver function from the graft, giving the native liver time to
recover and regenerate.
• The advantage over conventional transplantation is the temporary need for immunosuppression