Hepatic Encephalopathy : Hepatic Encephalopathy Dr .Umamaheshwara rao Hepatic encephalopathy (HE) : Hepatic encephalopathy (HE) a reversible neuro-psychiatric state
a complication of liver failure
pathogenesis is not understood fully
derangement of neurotransmitter system and metabolic system Pathogenesis : Pathogenesis No single metabolic derangement accounts for HE.
Failure of hepatic clearance of gut derived substances.
Hepatocellular failure or shunting.
Altered aminoacid metabolism.
Accumulation of unmetabolized ammonia 2ry to poor hepatic function or shunt.
Production of false neurotransmitters.
Activation of GABA-Benzo receptors by endogenous ligands.
Altered cerebral metabolism.
Disturbed activity of Na/K ATPase. Pathogenesis : Pathogenesis Scarring of liver( cirrhosis)
Obstruction of the passage of blood (liver)
Portal-systemic anastomoses ("shunts“)
Return to heart
Toxic substances enters brain
Impending hepatic coma Classification of hepatic encephalopathy : Classification of hepatic encephalopathy (World Congress of Gastroenterology 1998 in Vienna )
Type A (=acute) describes hepatic encephalopathy associated with acute liver failure;
Type B (=bypass) is caused by portal-systemic shunting without associated intrinsic liver disease;
Type C (=cirrhosis) occurs in patients with cirrhosis . Classification of hepatic encephalopathy : Classification of hepatic encephalopathy Type Aetiological factors
A(20%) Viral hepatitis,
Drug reacns &overdose.
B(100%) Portal systemic shunt,
Dietary protein intake,
Sepsis,Constipation. Neurotansmitters implicated in HE : Neurotansmitters implicated in HE Ammonia and Glutamate
GABA and Endogenous BZD
Others :Serotonin,Nitric oxide Ammonia and Glutamate : Ammonia and Glutamate Ammonia is produced from breakdown of
proteins, amino acids, purines, pyrimidines.
Liver converts ammonia to urea and glutamate by urea cycle
In HE, blood NH3 by 90% also brain levels
There is no urea cycle in the brain & NH3 is removed by diff pathway
NH3 leads to CMR and BBB permeability to NH3 Ammonia and Glutamate …contd : Ammonia and Glutamate …contd Hepatic encephalopathy
increase in cerebral ammonia
reduced glutamate receptors
glutamine accumulates Ammonia and Glutamate …contd : Ammonia and Glutamate …contd SOURCE : intestinal protein/bacteria
reduced hepatic removal
reduced muscle metabolism
EFFECTS: Astrocyte damage
BBB permeability (ICP) Manganese &false neurotransmitters : Manganese &false neurotransmitters Blood & Brain Mn levels increased in CLF
Normally produced dopamine & catecholamines mediated neuroamines are inhibited by false neurotransmitters (tyramine,octopamine)
Plasma levels of aromatic a.a &
branched chain a.a GABA & Endogenous BZD : GABA & Endogenous BZD GABA is principal inhibitory amine
It binds to specific GABA receptor in postsynaptic memb
Receptor also has binding site for BZD &barbiturates
GABA & Endogenous BZD are high in plasma &CSF of liver failure pts
These leads to hyperpolarisation &neuroinhibition Symptoms & Signs : Symptoms & Signs Earliest manifestations of hepatic encephalopathy is 'day-night Reversal‘
Impairment in spatial perception
Changed cognitive function –mild confusion to coma
Flapping tremor (asterixis )
Exaggerated deep tendon reflexes &sustained ankle clonus Acute liver failure : Acute liver failure (Depending on onset of encephalopathy & onset of jaundice)
Hyperacute - less than 7days
Acute - 7 to 28 days
Subacute - 28days to 6months
Chronic - more than 6 months Investigations : Investigations CSF analysis :cell count,protein,
Electroencephalogram :b/l synchronous
slowing of waves
Magnetic resonance spectroscopy
Neuropathology Treatment of Hepatic encephalopathy : Treatment of Hepatic encephalopathy Broadly divided into 3 areas
Identification & treatment of ppt factors
Interventions to reduce the production of & absorption of gut derived ammonia & other toxins
Prescription of agents to modify neurotransmitters Reduction of absorption and production of ammonia : Reduction of absorption and production of ammonia Protein restriction to 20g/day then increase 10g /3-5 days and
Supplementation with vegetable protein is important in patients
with low tolerance.(Related to fiber/protein ratio)
Reduction of endogenous (intestinal cells shedding) and dietary ammoniagenics by cathartics (Lactulose and Lactitol).
Dose titrated to 2-4 loose/acidic stools/day generally requiring 30-60grams/day.
Lactulose (10-30ml tid):
1- Decreases Intestinal PH. Favors growth of non-urease
2- Promotes movement of ammonia from blood to bowel
and decreased absorption.
Lactilol (0.3-0.5g/kg/day)–responds more quickly,less diarrhoea & flatulence Reduction of absorption and production of ammonia : Reduction of absorption and production of ammonia Antibiotics :
Neomycin (4-6 gr /day )for 5-7 days in acute cases
reduces ammonia formation in GIT
(careful in RF)
Metronidazole(200 mg Qid )
Rifaximin, or brand name Xifaxan, a derivative of rifamycin at a dose of 400 mg taken orally 3 times a day was as effective as lactulose or lactilol at improving hepatic encephalopathy symptoms. Similarly, rifaximin was as effective as neomycin and paromomycin. Rifaximin was better tolerated than both the cathartics and the other nonabsorbable antibiotics. . There are also concerns regarding the cost-effectiveness of the medication.
Purgation by enemas esp phosphate
Repopulation of bowel with non urease producing bacteria.
Erradication of H. pylori. Other support : Other support Supplementation with ornithine-aspartate to provide substrates for ammonia detoxification
Reduction of false neurotransmitters
Formulas rich in branched chain a.a and low in aromatic a.a.
Decreased activity of dopaminergic neurotransmitters taken care with bromocriptine or levodopa
Controversial results in the use of Flumazenil to block GABA-Benzo receptor (Increased endogenous production of benzo-like ligands). Slide 24: Management in Acute Liver Failure :
HE rapid in onset and associated with cerebral edema in later stages.
ALF with stage 3-4 HE should undergo elective ventilation , sedation with fentanyl, and paralysis if needed to avoid surges in ICP 2ry to psycomotor agitation(propofol).
Mannitol is the mainstay of therapy for cerebral edema in these cases.
Acetylcysteine and PGI2 have also proven beneficial.
Avoidance of hyopglycemia is paramount Other options : Other options Shunt occlusion
Hepatic transplantation Molecular adsorbent recirculating system(MARS) : Molecular adsorbent recirculating system(MARS) MARS is a device used to perform albumin liver dialysis.
The basic technical concept is based on conventional HD
It is a liver support system developed to support excretory liver function
It uses an albumin enriched dialysate to facilitate the removal albumin bound toxin(ABT) Schematic drawing of the molecular adsorbent recirculating system : Schematic drawing of the molecular adsorbent recirculating system USES OF MARS : USES OF MARS Acute fulminant liver failure
Acute on chronic liver failure (acute hepatorenal synd)
ALF with extensive liver resection for tumour
As temporary support in spontaneous recovery following abalative liver surgery
Liver transplant pt with primary graft dysfunction ISSUES TO RESOLVED(MARS) : ISSUES TO RESOLVED(MARS) Optimal timing of initiation & intensity of MARS
Optimum dose of albumin liver dialysis
Better approach b/w continous or intermittent References : : References : R.D.Miller.Miller’s anaesthesia ,6th ed 2005, P-2209-2229.
Sheila sherlock & James dooley.Diseases of the liver & biliary system,11th ed,P-93-110.
H .K. Tan: Hepatic excretory-assist device. Ann Acad Med Singapore 2004;33:329-335. Slide 31: THANKYOU