Hepatic encephalopathy

See also the separate Liver Failure, Cirrhosis and Hepatorenal Syndrome articles.

What is hepatic encephalopathy?

Hepatic encephalopathy is defined as a spectrum of neuropsychiatric abnormalities in patients with liver failure, after exclusion of other known brain disease. Hepatic encephalopathy can be subdivided into covert hepatic encephalopathy and overt hepatic encephalopathy.

Covert hepatic encephalopathy is a subclinical, less severe manifestation of hepatic encephalopathy and requires psychometric testing for diagnosis¹ . Covert hepatic encephalopathy has a significant impact on a patient's quality of life, including employment and driving performance, and is associated with increased admissions to hospital and with death² .

Features of hepatic encephalopathy include personality changes, intellectual impairment and reduced levels of consciousness. The pathogenesis of hepatic encephalopathy is uncertain but may be due to the passage of neurotoxins to the brain³ . Hepatic encephalopathy develops in up to 50% of patients with cirrhosis and is a feature of decompensated cirrhosis⁴ .

Common precipitants

• Acute kidney injury.

• Electrolyte imbalance.

• Gastrointestinal bleeding.

• Infection.

• Constipation.

• Sedative drugs - eg, opiates, benzodiazepines, antidepressants and antipsychotic drugs.

• Diuretics.

• High protein intake.

Hepatic encephalopathy symptoms (presentation)

Grading of hepatic encephalopathy⁵

• Patients with very mild hepatic encephalopathy may have normal memory, language and motor skills but may have impairment of attention and decision-making and may have impaired fitness to drive. These patients usually have normal function on standard mental state testing but abnormal psychometric testing.

• Patients with mild and moderate hepatic encephalopathy show decreased short-term memory and concentration with testing of mental state. They may also have a flapping tremor (asterixis), fetor hepaticus (a sweet musty aroma of the breath), hyperventilation and hypothermia.
  

West Haven Criteria⁶

Since the above grading system was developed - in 1998 by a World Congress of Gastroenterology working party - the West Haven Criteria was published. These have become the standard criteria to assist in the diagnosis of hepatic encephalopathy:

Grade 1

• Trivial lack of awareness.

• Euphoria or anxiety.

• Shortened attention span; impaired performance of addition or subtraction.

Grade 2

• Lethargy or apathy.

• Minimal disorientation for time or place.

• Subtle personality change.

• Inappropriate behaviour.

Grade 3

• Somnolence to semi-stupor, but responsive to verbal stimuli.

• Confusion.

• Gross disorientation.

Grade 4

• Coma.

Investigations⁶

• Psychometric tests - this are becoming increasingly useful in the diagnosis of minimal hepatic encephalopathy.

• Arterial or serum ammonia levels are raised and can help with diagnosis.

• Electroencephalogram (EEG): may show high-amplitude low-frequency waves and triphasic waves but these findings are not specific for hepatic encephalopathy.

• MRI/CT scanning can help to exclude other causes of altered mental function such as intracranial lesions.

• Visual evoked responses show classic patterns associated with hepatic encephalopathy.

Differential diagnosis

Other causes of encephalopathy, including:

• Intracranial lesions - eg, haemorrhage, cerebrovascular event, tumour.

• Infection - eg, meningitis, encephalitis, intracranial abscess.

• Metabolic - eg, hypoglycaemia, electrolyte imbalance, anoxia, acute kidney injury.

• Other causes of hyperammonaemia - eg, ureterosigmoidostomy, inherited urea cycle disorders.

• Toxic - eg, substance abuse, alcohol-related problems.

• Drugs - eg, sedative hypnotics, antidepressants, antipsychotic agents and salicylates.

• Post-seizure.

Hepatic encephalopathy treatment and management

• Early diagnosis and aggressive identification and management of precipitating factors⁷ .

• Antibiotics (eg, rifaximin, neomycin/paromomycin/metronidazole, or vancomycin) are often given empirically as infection is a common underlying cause.

• Methods to combat raised levels of ammonia. Lactulose/lactitol (a non-absorbable osmotic laxative that also helps convert ammonia to non-absorbable ammonium in the gastrointestinal tract), LOLA L-ornithine and L-aspartate preparation - increases the use of ammonia in the urea cycle to produce urea).

• Sedative drugs should be avoided

Restriction of protein intake was once thought to be beneficial, but this was not supported by further evidence. Adequate nutrition is essential; in cirrhosis, there is actually an increased requirement for protein⁸ .

Drug treatment

• The nitrogen load from the gut should be reduced using lactulose or bowel enemas⁹ . However, a systematic review found that there is insufficient evidence to support or refute the use of non-absorbable disaccharides for hepatic encephalopathy¹⁰ .

• Antibiotics - eg, rifaximin, neomycin/paromomycin/metronidazole, or vancomycin - are often given empirically on the basis of infection as an underlying cause⁶ .

• Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor complex in the brain, resulting in neural inhibition. A Cochrane review found low-quality evidence suggesting a short-term beneficial effect of flumazenil on hepatic encephalopathy in people with cirrhosis, but no evidence of an effect on all-cause mortality¹¹ .

• Hepatic encephalopathy may be associated with an impairment of dopaminergic neurotransmission. However, there is insufficient evidence that dopamine agonists are of benefit to patients with acute or chronic hepatic encephalopathy, or fulminant hepatic failure¹² .

• Hepatic encephalopathy may be caused by a decreased plasma ratio of branched-chain amino acids to aromatic amino acids. A Cochrane review found that branched-chain amino acids had a beneficial effect on hepatic encephalopathy but did not find any effect on mortality, quality of life, or nutritional parameters¹³ .

• Zinc may be given if there is a deficiency⁶ .

Hepatic encephalopathy prognosis

The prognosis of hepatic encephalopathy is dependent on the degree of liver failure, comorbidities and the timing of effective treatment, especially of precipitating factors. The development of hepatic encephalopathy in patients with cirrhosis is associated with a worse prognosis and may lead to frequent and severe relapses. Patients with overt hepatic encephalopathy in hospital have a 3.9-fold increased mortality risk¹⁴ .

Prevention

Rifaximin is recommended by the National Institute for Health and Care Excellence (NICE) as an option for reducing the recurrence of episodes of overt hepatic encephalopathy in people aged 18 years or older¹⁵ .