Hepatic Encephalopathy

Dr/ Mohammed Hussien Assistant Lecturer of

Gastroentrology & Hepatology Kafrelsheik University

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

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).

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.

•

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.

Classification Of Hepatic

Encephalopathy

Classification

Clinical features of HE:Grade 0:

Minimal HE:

Minimal changes in memory, concentration, intellectual functions and coordination.

No personality or behavioral changes.

No asterixis.

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.

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.

1 )According to the underlying disease, HE is subdivided

into

• Type A resulting from ALF• Type B resulting predominantly from portosystemicbypass or shunting• Type C resulting from cirrhosis

(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.

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.

•(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.

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.

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

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

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

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.

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.

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.

Neurotoxic effect of ammonia:

Astrocyte swelling and brain oedema.

Alter neuronal membrane permeability Alter neurotransmitter expression and neurotransmitter

receptor expression.

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

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.

serotonin, nitric oxide, oxygen free radicles and circulating opioid contribute to encephalopathy .

Other factors that affect neurotransmission include

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

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.

Management of HE:

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.

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.ProbioticsA recent, open-label study of either lactulose, probiotics, or notherapy 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].

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 ofHE

Glutaminase inhibitors

Portosystemic shunting up-regulates the intestinal glutaminasegene so that intestinal glutaminase inhibitors may be useful byreducing 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 advocatesfor its use. However, long-term ototoxicity, nephrotoxicity, andneurotoxicity make these agents unattractive for continuouslong-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 HEthat does not improve on any other treatment, but is not withoutits 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, casesdo occur where HE severely compromises the patient’s quality

oflife and cannot be improved despite maximal medical therapyand who may be LT candidates despite otherwise good liver status.• Large PSSs may cause neurological disturbances and

persistentHE, even after LT

PrognosisDepends 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.