Hepatic Encephalopathy

Dr/ Mohammed HussienAssistant Lecturer of Gastroenterology & Hepatology

Kafrelsheik University

Membership at American Collage of Gastroenterology (ACG)

Membership at Egyptian association for Research and training in Hepatogastroentrology

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).

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, lowalbumin, high bilirubin.

West Haven grading of mental state

0 no abnormalityI 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 changesIII Somnolence, semi stupor, confused, bizarre behaviour, responsive to stimuli, gross disorientation (wake but not aware)IV Coma , unable to test mental state.

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

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.

Pathogenesis

Management of HE:

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

Most current medications designed to treat the hyperammonimia.

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.

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.

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.

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

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

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

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

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.

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

Glutaminase inhibitorsPortosystemic 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

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

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).

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.

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

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.