What is Hepatic Encephalopathy. What is the Grading of Hepatic Encephalopathy. How to Diagnose Hepatic Encephalopathy . How to Treat Hepatic Encephalopathy.

1. Hepatic
Encephalopathy
Dr/ Mohammed Hussien
Assistant Lecturer of Gastroenterology & Hepatology
Kafrelsheik University
Membership at American Collage of Gastroenterology (ACG)
Membership at Egyptian association for Research and training in
Hepatogastroentrology

2. Definition:
• Hepatic encephalopathy (HE)
Transient and reversible neuropsychiatric manifestations usually found in patients with chronic
liver disease and portal hypertension. HE develops in 50%-70% of patients with liver cirrhosis.
• HE, accompanying the acute onset of sever hepatic dysfunction, is the hallmark of fulminant
hepatic failure (FHF).

3. According to the underlying disease, HE is subdivided
into
• Type A resulting from ALF
• Type B resulting predominantly from portosystemic bypass or shunting
• Type C resulting from cirrhosis
•
• (Diagnosis is mainly clinical, as routine liver biochemistry just confirm the
presence of liver disease and not the presence of encephalopathy) e.g. high PT, low
albumin, high bilirubin.

4. West Haven grading of mental state
0 no abnormality
I Euphoria, anxiety, lack of awareness & impaired addition or subtraction (Mode _ sleep
_ behavior)
II apathy (mild Confusion = Delayed Response) , disorientation for time, In appropriate
behavior, personality changes
III Somnolence, semi stupor, confused, bizarre behaviour, responsive to stimuli, gross
disorientation (wake but not aware)
IV Coma , unable to test mental state.

9. Precipitating Factor
▪ 1- GIT bleeding
▪ Commonly due to rupture esophageal varcies or bleeding & Peptic ulcer. –(Bleeding -7 Shock -7 ~ hepatic
perfusion).
▪ Protein load –metabolites---encephalopathy.
▪ 2- Diuretics (excessive diuresis)
▪ They lead to hypokalemic alkalosis ------NH3 production -----NH3 diffusion to brain, also diuretics lead to
hypovolemia.
▪ 3- Aspiration of ascitis this leading to (electrolytes disturbance).
▪ 4- Any infection.
▪ S- High dietary protein.
▪ 6- Hepatotoxicity (drugs - alcohol), opiates, zinc deficiency.
▪ 7- Severe vomiting or diarrhea -7 electrolyte & acid base disturbances.
▪ 8- Spontaneous bacterial peritonitis.
▪ 9- Constipation.
▪ 10- Any surgical procedure.
• TIPS insertion

10. Differential diagnosis of HE:
• Intracranial lesion
• Infections; meningitis, encephalitis, abscess
• Metabolic encephalopathy; hypoglycemia, electrolyte imbalance, anorexia, uremia.
• Toxic encephalopathy from alcohol intake or withdrawal; Wernicke encephalopathy
• Toxic encephalopathy from drugs as antidepressants, antipsychotics, salicylates.
• Post-seizure encephalopathy.

11. Pathogenesis

13. Management of HE:

14. General management recommendations:
*Exclude non hepatic cause
*Check arterial ammonia level
*Check precipitant of HE
*Avoid medications that depress C.N.S.function
*Patients with severe HE should be managed in ICU and undergo prophylactic
endotracheal intubation

15. Most current medications designed
to treat the hyperammonimia.

16. A.Diet:
Protein restriction may be appropriate in some patients immediately
following a sever flare of symptoms.
However, protein restriction is rarely justified in patients with
cirrhosis and persistent HE. Indeed, malnutrition is a more
serious clinical problem than HE for many of these patients.
▪ Most patients with mild chronic HE tolerate more than 60-80 gm
of protein /day
▪ Diet containing vegetable proteins is better tolerated than diet
rich in animal protein, especially red meat.
▪ Well-cooked chicken and fish in addition to vegetable protein are
better tolerated.

17. B.Cathartics:
1-Lactulose:
➢ It is non-absorbable disaccharides.
➢ It is metabolized in lactic and acetic acids which results in acidification of gastro-intestinal
lumen.
➢ It inhibits intestinal ammonia production by :
- Gut acidification favors conversion of ammonia to
urea and its passage from tissues to lumen
- Gut acidification inhibits ammonia producing coliform
bacteria leading to non ammoniagenic lactobacilli.
- It acts as cathartic, reducing colonic bacterial load.

18. DOSE:
Initial dose 30ml orally daily or twice daily.
It is to be increased as tolerated.
Patients should take sufficient dose as to have 2-4 loose stool/day.
SIDE EFFECTS:
Diarrhea, ileus, hypovoloemia, electrolyte disturbance and actually may induce flare of
encephalopathy.

20. 2-L-Ornithine L-Aspartate:
• It stimulates urea cycle loss of ammonia
• Both are substrates for glutamate transaminase glutamate
• Ammonia is subsequently used in conversion of glutamate to glutamine by
glutamine synthetase.
3-Zinc:
• Its deficiency is common in cirrhosis.
• It improves hyperammonimia by increasing activity of Ornithine transcaranylase
( an enzyme in urea cycle)
• The increase in ureagenesis loss of ammonia
• Dose: 600 mg orally 1 day

21. C.Antibiotics:
Neomycin and Metronidazole are administered in an effort to decrease the colonic
concentration of ammoniagenic bacteria. It is more beneficial in acute than chronic
HE
DOSE: for acute HE 1gm/6h
For chronic 1-2gm/24h
SIDE EFFECTS: ototoxicity, nephrotoxicity

22. Rifaximin: (non-absorbable derivative of Rifampin):
It has a broad spectrum anti-bacterial activity and thus may be an appropriate agent for
eliminating both anaerobic and aerobic bacteria that are capable of producing
ammonia.
▪ It is well tolerated
▪ It has not been found to contribute to clinically relevant bacterial resistance
▪ It relatively has high cost
DOSE: 400mg 3 times/day

23. D.Combination of Lactulose and
antibiotics:
▪ Has synergistic effect in reduction of ammonia
▪ Achieve significant faster improvement in the degree of HE
▪ Fewer days of hospitalization

24. E.Probiotics
A recent, open-label study of either lactulose, probiotics, or no
therapy in patients with cirrhosis who recovered from HE found fewer
episodes of HE in the lactulose or probiotic arms, compared to placebo,
but were not different between either interventions. There was no difference
in rates of readmission in any of the arms of the study.

25. BCAAs
• An updated meta-analysis of eight randomized, controlled trials (RCTs) indicated
that oral BCAA-enriched formulations improve the manifestations of episodic HE
whether OHE or MHE
• There is no effect of IV BCAA on the episodic bout of
HE

26. Glutaminase inhibitors
Portosystemic shunting up-regulates the intestinal glutaminase
gene so that intestinal glutaminase inhibitors may be useful by
reducing the amounts of ammonia produced by the gut.
• Neomycin
• This antibiotic still has its advocates and was widely used in the
• past for HE treatment; it is a known glutaminase inhibitor [107].
• Metronidazole
• As short-term therapy [108], metronidazole also has advocates
for its use. However, long-term ototoxicity, nephrotoxicity, and
neurotoxicity make these agents unattractive for continuous
long-term use

27. Albumin
• A recent RCT on OHE patients on rifaximin given
daily IV albumin or saline showed no effect on
resolution of HE, but was related to better
postdischarge survival

28. Flumazenil
• This drug is not frequently used. It transiently improves mental
• status in OHE without improvement on recovery or survival.
• The effect may be of importance in marginal situations to avoid assisted ventilation.
Likewise, the effect may be helpful in difficult differential diagnostic situations by
confirming reversibility (e.g., when standard therapy unexpectedly fails or when
benzodiazepine toxicity is suspected).

29. Adjuvant therapy
Neuropharmaceuticals: Given the neuropsychiatric symptoms of HE and considering
the disorders of the neurotransmitter system, certain neuropharmaceuticals have
started to attract attention. These are nootropic substances and benzodiazepine
antagonists. They can be applied in patients resistant to other therapies.
o Flumazenil: In 1985 the assumption that GABAergic neuroinhibition is
increased in HE led to the therapeutic use of the benzodiazepine antagonist
flumazenil (G. Bansky et al.) An improvement in the neuropsychiatric
symptoms of HE was achieved in 66% of patients. The recommended dosage
is 0.2-0.3 mg i.v. bolus, followed by 5 mg/ hour as i.v. infusion. Remarkable
arousal effects and unexpected long-term success (50 mg/day orally) were
described even in hepatic coma. In severity stage III of HE improvement
occurred in 93% of cases, and in stage IV the rate was 48%. Recently, a
metaanalysis showed that flumazenil improves clinical and
electroencephalographic findings regarding HE in cirrhotic patients.

31. Liver transplantation (LT)
• Liver Transplantation remains the only treatment option for HE
that does not improve on any other treatment, but is not without
its risks. The management of these potential transplant candidates as practiced in the
United States has been published
• Hepatic encephalopathy by itself is not considered an indication
for LT unless associated with poor liver function. However, cases
do occur where HE severely compromises the patient’s quality of
life and cannot be improved despite maximal medical therapy
and who may be LT candidates despite otherwise good liver status.
• Large PSSs may cause neurological disturbances and persistent
HE, even after LT

32. Prognosis
Depends on the extend of liver cell failure
▪ Best in chronic patients with extensive collateral circulation
▪ Worst in the acute hepatitis
▪ In cirrhosis outlook is poor in presence of ascites, jaundice, low serum
albumin
▪ Survival rate in cirrhotic patient after the first episode is 42% at 1 year and 23% at 3
years.