Hepatic encephalopathy, Hepatic stupor, hepatic coma, porto-systemic encephalopathy, hepato-cerebral encephalopathy

Table I.

Classification	Symptoms and physical findings
Minimal encephalopathy	Minimal changes in memory, evidence on psychometric testing, absence of detectable changes in personality and behavior
Grade I	Trivial lack of awareness, euphoria or anxiety, shortened attention span, impaired performance of addition or subtraction
Grade II	Lethargy or apathy, minimal disorientation for time or place, subtle personality change, inappropriate behavior, asterixis usually present
Grade III	Somnolence to semistupor, but responsive to verbal stimuli, confusion, gross disorientation, clonus, nystagmus, positive Babinski sign
Grade IV

Key management points

Because HE in patients with ESLD is usually triggered by precipitating factors such as infection, gastrointestinal bleeding, electrolyte abnormalities, and medication noncompliance, it is important to identify these factors and manage them accordingly. In addition to general supportive care, the following strategy should be taken when managing HE:

• Reduce ammonia production and absorption

• Increase ammonia excretion

• Target potential neurotransmitters, toxic substances

• Provide nutritional support

As mentioned above, HE in ESLD is not usually due to worsening liver disease; rather, it is a result of a precipitating factor.

2. Emergency Management

Patients with advanced HE (Grade III and IV) should be admitted to the intensive care unit.

Airway should be secured via endotracheal intubation to prevent aspiration.

Ventilator may be set to correct acid-base abnormalities if present.

Circulatory support is initiated first with volume repletion, but the use of vasopressors/inotropes may be required.

Treat sepsis with broad-spectrum antibiotics after cultures are obtained. Spontaneous bacterial peritonitis (SBP) is the most common infection.

Treatment directed towards lowering ammonia should be started.

In case of advanced HE that is due to acute hepatic failure, the focus should be on prevention and management of cerebral edema, which is the leading cause of mortality, as follows:

• General measures such as head-of-bed elevation to a 30-degree angle, and maintaining the patient’s neck in neutral position

• Endotracheal intubation for grade III and IV encephalopathy

• Measures to decrease ammonia level

• Minimize stimulation, including airway suctioning

• Avoid hypovolemia and hypervolemia

• Avoid hypercapnia and hypoxia

• Maintain intracranial pressure <15 mmHg if an ICP monitor is available

• Maintain cerebral perfusion pressure >50 mmHg

• If ICP monitoring is unavailable, then use other surrogate measures such as maintaining SVJO2 between 55-85% or A-V O2 difference between 4 and 6 or serial transcranial Doppler.

• Adequate use of sedatives and analgesics

In cases of proven intracranial hypertension/cerebral edema, the following should be done or considered:

• Mannitol boluses 0.5-1 g/Kg body weight as long as serum osmolarity is less than 320 mosm/L

• Induction of moderate hypothermia to 32-33 degrees C

• Maintain serum sodium level of 145 to 155 mEql/L using hypertonic saline

• Induce, with propofol or pentobarbital titrated to burst suppression of 5 to 10 cycles per second

• May consider indomethacin 25 mg intravenous bolus

• Plasmapheresis or molecular absorbent recirculating system (MARS)

• Total hepatectomy as bridge to transplantation (no liver may be better than a bad liver)

Management points not to be missed

Outline of management of HE includes:

• General supportive care

• Prompt identification and treatment of its precipitating factors, such as gastrointestinal bleeding, infection, electrolyte abnormalities, etc. Most episodes of HE reflect presence of precipitating factors rather than natural progression of liver disease.

• Reduce ammonia production and increase ammonia excretion as follows:

  Lactulose and lactitol (non-absorbable disaccharides, used currently as first-line therapy for HE): although commonly used, some studies have challenged their efficacy and no study so far has demonstrated positive effect on survival. Can be administered orally or rectally. Mechanism of action includes acidification of gut lumen, which favors conversion of ammonia to ammonium. which is less likely to be absorbed. Also this will modify gut flora favoring lactobacillus over urease and protease-splitting bacteria. In addition, the cathartic effect decreases transit time for ammonia precursors.

  Antibiotics such as metronidazole, neomycin or rifaximin. These work by modifying the gut flora as above. Rifaximin was recently approved by FDA for chronic HE. It was shown to decrease hospital admissions compared to placebos. In addition, it was shown to reduce ammonia level and improve EEG compared to those observed with lactitol. Neomycin was FDA approved for management of acute HE. Despite its poor absorption, chronic administration can result in nephrotoxicity and ototoxicity. Metronidazole is not FDA approved for management of HE. One study revealed it is as effective as neomycin at a dose of 250 mg orally twice a day. Concern for resistant
  C. diff colitis and neurotoxic effect has limited its use in patients with HE.

• Plasma ammonia-lowering devices and non-pharmacological intervention

  Hemodialysis and continuous renal replacement therapy, ultrafiltration with the use of high dialysate flow rate is an effective method of rapidly lowering serum plasma ammonia level. Avoid hemodialysis in patients with suspected intracranial hypertension as fluid shifts may worsen the cerebral edema.

  Molecular absorbent recirculating system (MARS) is a blood detoxification system based on albumin dialysis that removes protein-bound and water-soluble toxins. FDA approved for toxin removal in poisoning but not for HE. It is used in USA in acute hepatic failure due to drug overdose. Small studies have shown treatment with MARS improves HE; however, larger studies are needed

• Alternative pathway therapies

  Sodium benzoate and sodium phenylacetate. These have been shown to enhance the metabolism of ammonia. AMMONUL (10% sodium benzoate and 10% sodium phenylacetate) is FDA approved and routinely used for treatment of hyperammonemia in urea cycle disorders. One small study has shown benefit in treatment of HE. It is very costly, which limits its use.

  L-ornithine L-aspartate (LOLA). Despite multiple promising small studies, a recent randomized double-blinded placebo-controlled study failed to show its effect on ammonia or mortality.

  Ornithinephenylacetate. Animal studies have demonstrated enhanced conversion of ammonia to glutamine and subsequently trapping it as phenylacetylglutamine, which is excreted by the kidneys.

• Neurotransmitter blockade

  Flumazenil, a short-acting benzodiazepine antagonist that inhibits endogenous GABA substances, has been shown to improve HE but failed to show long-term benefit or long-term outcome.

• Nutritional and micronutrient supplementation

  Zinc, carnitine and/or branch chain amino acids may play a role in HE. Whenever possible, enteral nutrition without protein restriction should be started without delay.

Drugs and dosages

Lactulose orally 30 grams every 1-2 hours for goal of 3 or 4 soft bowel movements a day. Rectally 300 mls in 700 mls of water, retained for one hour, can be given every 4-6 hours.

Metronidazole 500 mg orally per day (250 mg BID)

Neomycin 1 gm every 6 hours up to 6 days in acute HE. 1-2 gm daily for chronic HE.

Rifaximin 550 mg orally BID

Flumazenil trial of 1-2 mg given over 3-5 minutes

3. Diagnosis

Diagnostic criteria

Hepatic encephalopathy is a diagnosis of exclusion, requiring detailed history, physical examination and laboratory investigation.

Similar symptoms may be seen in a variety of other metabolic processes, toxin ingestions, infectious processes, intracranial processes or drug overdose. In patients with known cirrhosis and portosystemic shunting, a known precipitating factor in a typical clinical presentation is sufficient to make a clinical diagnosis. Elevated serum ammonia is helpful but not essential to make the diagnosis. Serum ammonia has a poor correlation with the grade of encephalopathy.

Neuroimaging, EEG or lumbar puncture may be necessary to exclude other intracranial processes, especially if focal neurological deficit is present on examination.

It is necessary to exclude hypoxia, electrolyte abnormalities, azotemia or use of psychoactive drugs or toxins.

Diagnosis of minimal HE can be made only by psychometric testing.

When the diagnosis of HE is in doubt, empirical treatment is usually indicated, while precipitating factors are elucidated and treated appropriately.

Patients with grade III and IV HE are admitted to the intensive care unit.

Diagnostic tests

When a patient presents with possible HE, the following testing should be obtained:

• CBC with differentials

• ABG

• Electrolytes, BUN, Cr, Ca, Mg, PO4

• Liver function testing

• Amylase, lipase

• Ammonia

• Blood, urine cultures with urinalysis

• Diagnostic paracentesis, cell count, gram stain and culture of ascitic fluid

• EEG, CT or MRI of head and/or lumbar puncture may be indicated to rule out other causes, especially if there are focal neurological deficits or seizures.

• Abdominal imaging if there is any evidence of intra-abdominal process, such as perforated bowel or pancreatitis

Elevated ammonia level can be helpful but not essential in diagnosing HE.

Pathophysiology

There is not a single clear etiology that accounts for the occurrence of HE. However, current understanding suggests that HE is a result of complex interaction between ammonia, inflammation, altered neurotransmission pathways and cerebral hemodynamic dysautoregulation.

Ammonia is the most recognized factor that leads to HE in acute or chronic liver disease. Astrocytes rather than neurons have been demonstrated to be the most susceptible to the effect of hyperammonemia, but neurons can still be affected by the loss of homeostatic support provided by affected astrocytes. Astrocyte swelling is caused by intracellular hyperosmolarity produced by the metabolism of ammonia to glutamine, or by glutamine-induced mitochondrial dysfunction.

Ammonia is thought to result in both cytotoxic and vasogenic brain edema due to the cerebral energy failure, excessive intracellular accumilation of glutamine and alteration in aquaporin-4 integral membrane proteins.

Inflammation is a synergistic factor in modulating the cerebral effect of ammonia, and several inflammatory mediators can be attributed to the development and worsening of HE.

Impaired cerebral autoregulation and reduced cerebral blood flow may also lead to HE.

The contributive role of inflammation, altered neurotransmission pathways and cerebral hemodynamic dysautoregulation may account for why HE is present in some patients despite relatively low ammonia levels.

Table II describes precipitating factors and underlying mechanisms in HE.