1. Hepatic Encephalopathy
Nick Harper

2. “A neuropsychiatric syndrome
caused by hepatic insufficiency due
to acute or chronic liver disease”
– personality changes
– Intellectual impairment
– reduced level of consciousness
– altered neuromuscular activity

3. Classification
(World congress of gastroenterology 1998)
• Type A “Acute liver failure”
• Type B “portal systemic Bypass and no
intrinsic hepatocellular disease”
• Type C “Cirrhosis and portal hypertension”
Episodic, persistent, minimal

4. Epidemiology
• Prevalence 1.4 per 100,000 population (UK
2008)
• 70% of patients with cirrhosis
• 1 year survival 42%
• 3 year survival 23%

5. GABA
Osm

6. Serum ammonia raised in 90% of cases.
Not all hyperammonaemia is associated with encephalopathy

7. EEG
• Stage I – III triphasic
waves (5Hz) over
frontal lobes
• Stage IV slow delta
wave

8. PSE index (Conn 1977)
• Mental state
• Arterial ammonia
levels
• Degree of asterixis
• EEG scoring
• Number connection
test result
•Mental state, EEG and
NCT not independent
variables
•Arbitrary multplicator
used for mental state
•NCT and EEG are given
arbitrary units
•No age correction used
for NCT

9. West Haven criteria
(Conn score)
Grade 1: sleep reversal, mild lack of awareness,
shortened attention span
Grade 2: lethargy, poor memory, personality
change, asterixis
Grade 3: Somnolence, confusion, disorientation,
hyper-reflexia, nystagmus, clonus, rigidity
Grade 4: Stupor and coma

10. Reduce production
and absorption of
ammonia in the gut

11. Non absorbable disaccharides
(Lactulose)
• Increase bowel transit
• Ammonia to ammonium (not absorbed)
• GI effects, dehydration, non compliance
• Recurrence of hepatic encephalopathy over
14 months (Sharma et al 2009)
– Placebo 46.8%
– Lactulose 19.6%

13. Neomycin
• Aminoglycoside
• Reduce
encephalopathy
inducing bacterial
waste products
• Ototoxicity
• Nephrotoxicity

15. Rifaximin
• Antibiotic – Rifamycin class
• Wide spectrum
• Inhibits bacterial DNA dependent
RNA polymerase
• Very poorly absorbed (<0.4%)
• Maintain high concentrations inside the gut

17. Mas et al 2003 (Journal Hepatology)
• Prospective, randomised, double blind, double
dummy, controlled trial
• Grade I-III HE
• n=103
• Rifaximin Vs Lactitol

18. Ammonia

19. EEG

20. PSE score

21. Bass et al 2012 NEJM
• Phase 3 multicentre, randomised, double blind,
placebo controlled trial
• Rifaximin Vs Placebo
• n=299
• 2 episodes of hepatic encephalopathy in last 6 months
• Time to first breakthrough of encephalopathy (grade 2
or above)
• 6 month follow up

22. Placebo Rifaximin
encephalopathy 46% 22%
Hospitilisation 22.6% 13.6%
Mortality 7% 6%

23. • FDA approval 2010
– “reduction in risk of overt hepatic encephalopathy
recurrence” 550mg PO BD
• Mostly Child-Pugh A/B cirrhosis
• Dual therapy – 90% also had lactulose
• Not currently approved by MHRA

24. Current treatment
• Lactulose
– lack of good evidence but used since 70s
• Rifaximin
– More effective at reducing recurrence (FDA)
– More effective in initial treatment
– No change in overall mortality
– Not licensed for encephalopathy in UK
– £9.20 per day (BNF cost)