Approach

This condition is a diagnosis of exclusion and the manifestations may be subtle. A high index of suspicion for HE as a possible diagnosis should be maintained in any patient with acute or chronic hepatic dysfunction.

In patients with chronic liver disease, a precipitating factor may be causing the development of HE, such as hypovolaemia, gastrointestinal bleeding, infection, electrolyte disturbance (hypokalaemia, hyponatraemia) and renal failure, sedative or opioid ingestion, hypoxia, hypoglycaemia, excessive dietary protein intake, constipation, acute hepatic or portal vein thrombosis, or recent placement of a transjugular intra-hepatic portosystemic shunt (TIPS).[1][16][17][18]

The diagnosis and staging of HE is based on clinical examination. Investigations are necessary to exclude other causes of mental status alteration.[1] These include infection, electrolyte abnormalities (sodium, calcium, and potassium), glucose abnormalities, hypoxaemia, uraemia, toxin exposures (alcohol or sedative medications), and primary central nervous system abnormalities, such as bleeding or infection.

History

If possible, a full history should be taken to establish whether there is a precipitating cause or other cause of mental state alteration. It may be necessary to take a collateral history from a carer, relative, or friend.

Patients may describe symptoms of sleep disturbance (particularly excessive daytime sleepiness); personality changes such as apathy, irritability, and disinhibition; mood changes including euphoria and anxiety; and shortened attention span. As the condition progresses, patients become disoriented in space and time. They may become acutely confused, behave inappropriately, or demonstrate obvious personality change. Motor disturbances such as asterixis and dyspraxia develop. Somnolence, gross confusion, and bizarre behaviour may be followed by unconsciousness or coma.[1]

Patients, or, in case they are confused, their carers/family members, should be asked whether they have had any previous episodes of HE. After an episode of overt (grade 2, 3, or 4) HE, there is a 40% risk of recurrence within the next year.[1]

Examination

A full physical examination should be carried out to look for signs of precipitating factors and other causes of mental state alteration. Physical findings of cirrhosis include jaundice, ascites, palmar erythema, oedema, and spider telangiectasias. An enlarged liver may be seen in early viral hepatitis. Jaundice may be present.

Altered reflexes and nystagmus also may be present. Hyper-reflexia and a positive Babinski sign may occur. Extrapyramidal symptoms such as muscle rigidity, bradykinesia, hypokinesia, slow monotonous speech, and parkinsonian-like tremor are common.[1]

Asterixis is often present.[1]

In patients with cirrhosis and no history of overt HE, screening for covert HE should be carried out. There is no gold standard and little data regarding which test(s) should be used for this. The Animal Naming Test (i.e., the number of animals listed in 60 seconds, no equipment required) is the only bedside test to date and has shown promising results, although further validation is needed.[2]

Some patients may not express both mental (cognitive and behavioural) and motor signs of HE. Others express both, but these do not develop in parallel, making staging HE a challenge.

Initial investigations

Serum electrolytes, liver tests, coagulation profile, urea and creatinine, full blood count, serum glucose, inflammatory markers (e.g., C-reactive protein), thyroid-stimulating hormone, blood alcohol level, arterial or venous blood gas, urine toxin screen, urine culture, and blood cultures should be ordered.[2]

There has been much debate about the use of ammonia measurement in clinical practice.[21][22][23]​​​​ Blood ammonia levels correlate with the severity of HE, but not all cases of hyperammonaemia are associated with HE.[2]​ High ammonia levels alone do not have diagnostic, staging, or prognostic value for patients with HE with chronic liver disease.[1]​[22]​ However, a normal value warrants diagnostic re-evaluation.[1]​ Testing may be helpful in patients with undifferentiated coma for which low ammonia levels make HE less likely.[22]​ European guidelines recommend checking plasma ammonia levels in all patients with delirium/encephalopathy and liver disease, as they are considered to have a high negative predictive value in relation to a working diagnosis of HE and a normal value would bring the diagnosis of HE into question.[2]

Imaging studies

A head computed tomography (CT) or magnetic resonance imaging (MRI) scan may help to rule out other diagnoses or check for precipitating causes. While they may detect brain oedema and atrophy, these changes are neither sensitive nor specific for HE. In patients with delirium/encephalopathy and liver disease, brain imaging by CT or MRI should be performed if there are diagnostic doubts or non-response to treatment. It is always warranted if there is clinical suspicion of intracerebral haemorrhage, stroke, or a space-occupying lesion.[2] The risk of intracerebral haemorrhage is increased at least fivefold in this patient group.[1] The yield of a head CT is low in patients with cirrhosis and recurrent HE.[24]

An upper-quadrant abdominal ultrasound should be considered in all patients with unexplained acute decompensation, as acute portal or hepatic vein thrombosis can be the cause.

Other investigations

An electroencephalogram (EEG) may help in diagnosing mild HE and in excluding occult seizure activity in comatose patients.[2] HE may be associated with a decrease in brain wave frequency and amplitude.

In patients with ascites, a diagnostic paracentesis should also be performed to rule out spontaneous bacterial peritonitis, which may precipitate HE.

Lumbar puncture might be considered to exclude meningitis as a cause of altered mental status in appropriate settings.

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