Hepatic encephalopathy by Dr: Mohammed Hussien Ahmed

dr Mohammed Hussien ( assistant Lecturer of Gastroenterologist and Hepatology at Kaferelsheik University Egypy) illusterating one of Major complication of Cirrhosis --H.E

1. Hepatic Encephalopathy
Dr/ Mohammed Hussien
Assistant Lecturer of
Gastroentrology &
Hepatology
Kafrelsheik University

2. Functions of the Liver
•Main functions include:
•Metabolism of CHO, protein, fat
•Storage/activation vitamins and minerals
•Formation/excretion of bile
•Steroid metabolism, detoxifier of drugs/alcohol
•Action as (bacteria) filter and fluid chamber
•Conversion of ammonia to urea
•Gastrointestinal tract significant source of ammonia
•Generated from ingested protein substances that are deaminated by colonic
bacteria
•Ammonia enters circulation via portal vein
•Converted to urea by liver for excretion

3. Definition:
•Hepatic encephalopathy (HE) encompasses a wide
array of 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).

4. EASAL…..2014
•Hepatic encephalopathy is a brain dysfunction caused by liver
insufficiency and/or PSS; it manifests as a wide spectrum of
neurological or psychiatric abnormalities ranging from
subclinical alterations to coma
•Its occurrence is a poor prognostic indicator without liver
transplantation
•HE of cirrhosis and FHF share many of the same pathogenic
mechanisms. However, brain oedema plays a much more
prominent role in FHF than cirrhosis.
•

5. West Haven grading of mental
state
•0 no abnormality
•I Euphoria, anxiety, lack of awareness &
impaired addition or subtraction
•II apathy , disorientation for time, In
appropriate behavior, personality changes
•III Somnolence, semi stupor, confused, bizarre
behaviour, responsive to stimuli, gross disorientation
•IV coma , unable to test mental state.

6. Classification Of
Hepatic
Encephalopathy
Classification

10. Clinical features of HE:
Grade 0:
Minimal HE:
Minimal changes in memory, concentration,
intellectual functions and coordination.
No personality or behavioral changes.
No asterixis.

11. subclinical
Multivariate analysis shows that male sex, the
Child-Pugh score (B/C) and the presence of varices,
together with five statements from the Sickness
Impact Profile (SIP) identify patients at risk.

12. The five SIP statements found to have have independent
predictive value for subclinical hepatic encephalopathy are:
I.I spend much of the day lying down in order to
rest.
II.I’m confused and start several actions at a time.
III.I forgot a lot.
IV.I have difficulty doing handwork.
V.I’m not working at all.

17. 1( 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

18. )2( According to the severity of
manifestations.
•The continuum that is HE has been arbitrarily subdivided. For
clinical and research purposes, a scheme of such grading is
provided.
•Operative classifications that refer to defined functional
impairments aim at increasing intra and inter-rater
reliability and should be used whenever possible.

19. You Can Know that
•The expression hepatic encephalopathy (HE) is a collective
term covering five clinical forms of disease:
• (1.) Reye’s syndrome,
• (2.) fulminant liver failure,
• (3.) enzyme deficiency of the urea cycle,
• (4.) pseudo-portosystemic encephalopathy PSE,
• (5.) portosystemic encephalopathy PSE.

20. •)3( According to its time course, HE is subdivided
into
• Episodic HE
• Recurrent HE denotes bouts of HE that occur with
a
•time interval of 6 months or less.
• Persistent HE denotes a pattern of behavioral
•alterations that are always present and
interspersed
•with relapses of overt HE.

21. Reye’s syndrome
•denotes an acute, noninflammatory syndrome with acute
liver failure and encephalopathy. Such a “hepatocerebral
syndrome” is fatal in 3060% of cases.
•It is observed in infants and children (mainly between the
ages of 6 and 14 years) after feverish infection particularly
of the respiratory organs. This disease is seldom observed in
adults.
• The cause is still not completely clear, even though a virus
infection (influenza A or B, Coxsackie B2, varicella), the
intake of acetylsalicylic acid and mycetism are all considered
to be responsible.

23. Some investigators contend that HE is a disorder of
astrocyte function.
Astrocytes account for about one third of cortical volume.
They play a key role in:
•Regulation of blood-brain barrier
•Maintaining electrolyte homeostasis
•Providing nutrients and neurotransmitter precursors to
neurons
•Detoxification of number of chemicals including ammonia

24. A number of factor occurring alone or in combination have been
implicated in the development of HE which may differ in
acute and chronic liver disease. These factors include:
- Production of neurotoxins
- Altered permeability of blood-brain barrier
- Abnormal neurotransmission
The best described neurotoxin in HE is
Ammonia

25. Ammonia hypothesis:
Ammonia is produced mainly in colon by the bacterial
degradation of proteins and other nitrogen based
products.
Enterocytes also convert glutamine Glutaminase
glutamate and ammonia
Normally, ammonia is detoxified in the liver by
conversion to urea by Kerbs-Henseleit cycle.
Ammonia is also consumed in the conversion of glutamate
glutaminesynthtase glutamine

26. In liver cirrhosis hyper-ammonemmia occurs due to:
•Decreased mass of functioning hepatocytes
•Porto-systemic shunting may divert ammonia containing blood
away from the liver.

27. Skeletal muscles are important sites for ammonia metabolism
I liver cirrhosis due to increase in glutamine synthetase activity
in the muscle.
However, the muscle wasting that is observed in advanced
cirrhosis may potentiate hyperammonimia.

28. Brain astrocytes also posses glutamine synthetase. However
brain is unable to increase glutamine synthetase activity in
the setting of hyperammonimia.
Thus the brain remains vulnerable to the effect of
hyperammonimia.

29. Neurotoxic effect of ammonia:
Astrocyte swelling and brain oedema.
Alter neuronal membrane permeability

Alter neurotransmitter expression and neurotransmitter
receptor expression.

30. GABA hypothesis:
•It is a neuroinhibitory substance produced in GIT.
•GABA receptor complex contains binding sites for GABA
benzodiazepines and barbiturates.
•It is suggested that there is changing in perception regarding activity
of GABA receptor complex in cirrhosis
•It was believed that there were increased levels of GABA and
endogenous benzodiazepines in plasma.
•These chemicals cross blood brain barrier.
•Binding of GABA and benzodiazepines to a supersensitive GABA
receptor complex permitted influx of chloride into postsynaptic
neurons generation of neuro-inhibitory potentials

31. Recently it is postulated that GABA receptor complex contains
binding site for neurosteroids. Today some investigators
contend that neurosteroids plays a key role in HE.
Neurotoxins like ammonia and manganese stimulates
conversion of cholesterol to pregnenolone to neurosteroids.
The neurosteroids released from astrocyte and bind to their
receptors in the GABA receptor complex and increase inhibitory
transmission.

32. serotonin, nitric oxide, oxygen free
radicles and circulating opioid
contribute to encephalopathy.
Other factors that affect
neurotransmission include

33. Precipitating factors:
•Renal failure
•GI bleeding
•Sepsis
•Hyponatremia and hypokalemia
•Dehydration (water restriction, paracentesis, diarrhoea and
diuretics)
•Constipation
•Excess protein load
•TIPS insertion
•Alcohol misuse
•CNS active drugs
•Surgery

35. 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.

36. Management of HE:

39. Approach considerations:
It depends upon the severity of changes in mental status
and upon certainty of the diagnosis. As an example;
-A patient with known cirrhosis and complains of mild
decreased concentration might be served by an empiric
trial of Lactulose or Rifaximin and follow up to check its
effect.
-Patients presenting with hepatic coma require a different
approach.

40. 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

41. Most current medications designed to
treat the hyperammonimia.

42. 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.

43. 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.

44. 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.

46. 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

47. 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

48. 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

49. 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

50. 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 [106].

51. 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

52. 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

53. 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

54. 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).

55. 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.

57. 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

58. 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.