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

Hepatic encephalopathy is defined as a spectrum of neuropsychiatric abnormalities in patients with liver failure, after exclusion of other known brain disease. Features of hepatic encephalopathy include personality changes, intellectual impairment and reduced levels of consciousness.¹ The pathogenesis of hepatic encephalopathy is uncertain but may be due to the passage of neurotoxins to the brain.¹

Common precipitants¹

• Renal failure.
• Electrolyte imbalance.
• Gastrointestinal bleeding.
• Infection.
• Constipation.
• Sedative drugs, e.g. opiates, benzodiazepines, antidepressants and antipsychotic drugs.
• Diuretics.
• High protein intake.

Presentation¹

• 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.

Investigations

• Psychometric tests - this are becoming increasingly useful in the the diagnosis of minimal hepatic encephalopathy.
• Arterial or serum ammonia levels are raised and can help with diagnosis.²
• Electroencephalogram (EEG): may show high-amplitude low-frequency waves and triphasic waves, but these findings are not specific for hepatic encephalopathy although recent work suggests EEG may be useful prognostically.³
• MRI/CT scanning can help to exclude other causes of altered mental function such as intracranial lesions.²
• Visual evoked responses show classic patterns associated with hepatic encephalopathy.

Differential diagnosis¹

Other causes of encephalopathy, including:

• Intracranial lesions, e.g. haemorrhage, cerebrovascular event, tumour.
• Infection, e.g. meningitis, encephalitis, intracranial abscess.
• Metabolic, e.g. hypoglycaemia, electrolyte imbalance, anoxia, renal failure.
• Other causes of hyperammonaemia, e.g. ureterosigmoidostomy, inherited urea cycle disorders.
• Toxic, e.g. substance abuse, alcohol-related problems.
• Drugs, e.g. sedative hypnotics, antidepressants, antipsychotic agents and salicylates.
• Post-seizure.

Management

• Early diagnosis and aggressive identification and management of precipitating factors.⁴
• Avoidance of sedative drugs.

Restriction of protein intake was not found to be beneficial in one trial.⁵ Adequate nutrition is essential and restricting protein intake may cause or aggravate malnutrition.

Drug treatment

• The nitrogen load from the gut should be reduced using lactulose or bowel enemas.⁶ However, a systematic review found that there is insufficient evidence to support or refute the use of non-absorbable disaccharides for hepatic encephalopathy.⁷
• Antibiotics: neomycin may also be used to lower amino acid production by decreasing the concentration of ammonia-forming colonic bacteria.^6,8 Other antibiotics have also been used, e.g. metronidazole, vancomycin and the quinolones. Rifaximin is an antibiotic licensed for the treatment of traveller's diarrhoea in the USA. It is based on rifamycin and has little, if any, systemic absorption. It has been shown to be beneficial in patients with minimal hepatic encephalopathy and is undergoing further studies.⁹
• Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor complex in the brain, resulting in neural inhibition. Flumazenil (a benzodiazepine antagonist) has been shown to have a significant beneficial effect on short-term improvement of hepatic encephalopathy in patients with cirrhosis, but with no significant effect on recovery or survival.¹⁰
• 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 failure.¹¹
• Hepatic encephalopathy may be caused by a decreased plasma ratio of branched-chain amino acids to aromatic amino acids. There is also no evidence that branched-chain amino acids have a significant beneficial effect on patients with hepatic encephalopathy.¹²

Prognosis

The prognosis is dependent on the degree of liver failure, comorbidities and the timing of effective treatment, especially of precipitating factors.

Document references

1. Wolf DC, Encephalopathy, Hepatic, Medscape, Aug 2010
2. Wolf DC; Cirrhosis, Medscape, Sep 2011
3. Marchetti P, D'Avanzo C, Orsato R, et al; Electroencephalography in patients with cirrhosis. Gastroenterology. 2011 Nov;141(5):1680-1689.e2. Epub 2011 Jul 18. [abstract]
4. Shawcross D, Jalan R; Dispelling myths in the treatment of hepatic encephalopathy. Lancet. 2005 Jan 29-Feb 4;365(9457):431-3. [abstract]
5. Cordoba J, Lopez-Hellin J, Planas M, et al; Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol. 2004 Jul;41(1):38-43. [abstract]
6. Heidelbaugh JJ, Sherbondy M; Cirrhosis and chronic liver failure: part II. Complications and treatment. Am Fam Physician. 2006 Sep 1;74(5):767-76. [abstract]
7. Als-Nielsen B, Gluud LL, Gluud C; Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ. 2004 May 1;328(7447):1046. Epub 2004 Mar 30. [abstract]
8. Schuppan D, Afdhal NH; Liver cirrhosis. Lancet. 2008 Mar 8;371(9615):838-51. [abstract]
9. Bajaj JS, Heuman DM, Wade JB, et al; Rifaximin improves driving simulator performance in a randomized trial of Gastroenterology. 2011 Feb;140(2):478-487.e1. Epub 2010 Sep 21. [abstract]
10. Als-Nielsen B, Gluud LL, Gluud C; Benzodiazepine receptor antagonists for hepatic encephalopathy. Cochrane Database Syst Rev. 2004;(2):CD002798. [abstract]
11. Als-Nielsen B, Gluud LL, Gluud C; Dopaminergic agonists for hepatic encephalopathy. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD003047. [abstract]
12. Als-Nielsen B, Koretz RL, Kjaergard LL, et al; Branched-chain amino acids for hepatic encephalopathy. Cochrane Database Syst Rev. 2003;(2):CD001939. [abstract]