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 causes a range of symptoms from subtle cognitive changes to severe confusion, personality alterations, disorientation, lethargy, and coma.¹

Hepatic encephalopathy is thought to be caused by the accumulation of neurotoxins in patients with liver dysfunction.¹

Epidemiology

Studies suggest that hepatic encephalopathy is diagnosed in between 44 and 51% of people with cirrhosis. However, it is thought that up to 80% of people with cirrhosis may have hepatic encephalopathy with more subtle symptoms.¹

Causes of hepatic encephalopathy

Hepatic encephalopathy can arise directly from chronic liver disease or from portosystemic shunts where the portal circulation is redirected into the systemic circulation, bypassing the liver and therefore causing a build-up of toxic metabolites.¹ Ammonia is the main toxin causing hepatic encephalopathy; other factors include high levels of bile acids in the CSF, manganese accumulation in the basal ganglia, and oxidative stress. Hepatic encephalopathy causes brain cell destruction but brain cell destruction is also one of the underlying mechanisms that causes hepatic encephalopathy - inflammation, in the presence of cirrhosis, appears to lead to tumour necrosis factor (TNF) production which contributes to hepatic encephalopathy development.²

Causes of liver failure include:

• Acute liver failure:

  • Viral hepatitis.

  • Paracetamol overdose.

  • Ischaemia eg following sepsis.

• Chronic liver failure (cirrhosis):

  • Alcohol overuse.

  • Chronic viral hepatitis.

  • Haemochromatosis.

  • Non-alcoholic fatty liver disease.

  • Wilson's disease.

  • Alpha-1 antitrypsin deficiency.

In cirrhosis, hepatic encephalopathy is often triggered by a specific precipitant including:

• Acute kidney injury.

• Electrolyte imbalance.

• Gastrointestinal bleeding.

• Infection.

• Constipation.

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

• Diuretics.

Hepatic encephalopathy symptoms (presentation)

Symptoms include cognitive changes, personality alterations, disorientation, lethargy, and coma. Extrapyramidal signs associated with HE have been clearly documented - these can be episodic and associated with bouts of hepatic encephalopathy; however, they can also be progressive and appear more similar to Parkinson's disease.³

Grading of hepatic encephalopathy - West Haven Criteria¹

The West Haven criteria have become the standard criteria to assist in the diagnosis of hepatic encephalopathy:

Grade 0

• Minimal 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.

Grading of hepatic encephalopathy - World Health Congress of Gastroenterology criteria

The World Health Congress of Gastroenterology criteria categorise hepatic encephalopathy based on its underlying aetiology: offering a comprehensive approach to the management of hepatic encephalopathy.

• Type A (acute): Hepatic encephalopathy associated with acute liver failure, typically with cerebral oedema.

• Type B (bypass): Hepatic encephalopathy caused by portal-systemic shunting, without associated intrinsic liver disease.

• Type C (cirrhosis): Hepatic encephalopathy in patients with cirrhosis, which is further subdivided into episodic, persistent, and minimal encephalopathy.

Grading of hepatic encephalopathy - covert vs overt

There can be challenges in diagnosing subtle changes in early very mild hepatic encephalopathy. The term covert hepatic encephalopathy can be used to describe minimal hepatic encephalopathy including grades 0 and 1 in the West Haven criteria.

Investigations¹⁴

• LFTs and renal function.

• 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 diagnosis¹

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 management¹⁵⁶

• Management usually involves ammonia lowering and supportive care.

• Methods to combat raised levels of ammonia include lactulose/lactitol and rifaximin.

• L-Ornithine L-Aspartate (LOLA) is a drug that can reduce ammonia and has been shown to be beneficial. ²

• Trials of other drugs have not shown significant benefit in studies, although further studies are taking place.⁷

• Nutritional support, including regular small meals. Fasting 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 protein.⁸Some patients experience worsening of their symptoms with meat intake - vegetable proteins are a useful alternative.¹

• Good hydration and electrolyte correction.

• Sedative drugs should be avoided wherever possible. If patients are agitated then a safe environment and restraint is often preferable to sedation.

• Other than ammonia-increasing medication, there is no evidence of benefit from other drug treatments.

• Surgical procedures to close portosystemic shunts can be effective where the hepatic encephalopathy is caused by a shunt and is not responding to supportive management.

• Liver transplantation may be offered; where liver transplantation occurs, reversal of the cognitive effects of hepatic encephalopathy may be seen within 5 years.¹

Hepatic encephalopathy prognosis

Patients with cirrhosis and hepatic encephalopathy have a risk of recurrence. Neurological deficits may persist despite an apparent return to normality; these deficits tend to be worse in patients who have had multiple episodes of hepatic encephalopathy.¹

A single episode of overt hepatic encephalopathy increases mortality risk independently of other organ failures. The prognosis tends to be worse in hepatic encephalopathy associated with liver failure. Studies have shown a 44% survival at 12 months and 35%¹ survival at 24 months in those needing hospitalisation for their hepatic encephalopathy.

It is advised that all patients with a history of overt hepatic encephalopathy or with minimal hepatic encephalopathy avoid driving.¹

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 older.⁹

Lactulose is recommended for all patients with cirrhosis after a single episode of hepatic encephalopathy.¹

Patients should adhere to a regulated diet, high in protein, and avoid long periods of fasting. A bedtime snack is often recommended. ¹