Hepatic encephalopathy

Synonyms

1

Overview

Hepatic encephalopathy is a syndrome observed in some patients with cirrhosis. It is defined as a spectrum of neuropsychiatric abnormalities in patients with liver dysfunction, when other known brain disease has been excluded. Signs and symptoms may be debilitating, and they can begin mildly and gradually, or occur suddenly and severely. They may include personality or mood changes, intellectual impairment, abnormal movements, a depressed level of consciousness, and other symptoms. There are several theories regarding the exact cause, but development of the condition is probably at least partially due to the effect of substances that are toxic to nerve tissue (neurotoxic), which are typically present with liver damage and/or liver disease. Treatment depends upon the severity of mental status changes and upon the certainty of the diagnosis.

Symptoms

The mildest form of hepatic encephalopathy is difficult to detect clinically, but may be demonstrated on neuropsychological testing. It is experienced as forgetfulness, mild confusion, and irritability. The first stage of hepatic encephalopathy is characterised by an inverted sleep-wake pattern (sleeping by day, being awake at night). The second stage is marked by lethargy and personality changes. The third stage is marked by worsened confusion. The fourth stage is marked by a progression to coma.

More severe forms of hepatic encephalopathy lead to a worsening level of consciousness, from lethargy to somnolence and eventually coma. In the intermediate stages, a characteristic jerking movement of the limbs is observed (asterixis, "liver flap" due to its flapping character); this disappears as the somnolence worsens. There is disorientation and amnesia, and uninhibited behaviour may occur. In the third stage, neurological examination may reveal clonus and positive Babinski sign. Coma and seizures represent the most advanced stage; cerebral oedema (swelling of the brain tissue) leads to death.

Encephalopathy often occurs together with other symptoms and signs of liver failure. These may include jaundice (yellow discolouration of the skin and the whites of the eyes), ascites (fluid accumulation in the abdominal cavity), and peripheral edema (swelling of the legs due to fluid build-up in the skin). The tendon reflexes may be exaggerated, and the plantar reflex may be abnormal, namely extending rather than flexing (Babinski's sign) in severe encephalopathy. A particular smell (foetor hepaticus) may be detected.

Causes

Hepatic encephalopathy is not an inherited condition, so an individual who has it cannot pass it on to his/her children. It is brought on by chronic liver failure, particularly in alcoholics with cirrhosis.

Although there are many theories and possibilities regarding what exactly causes hepatic encephalopathy, it is thought that one of the main causes is the accumulation of ammonia in the blood, which the liver, damaged by alcoholic liver disease, cannot remove. Researchers have found that ammonia alters the expression of certain genes; the genes that may be affected carry instructions for brain proteins. When the instructions in these genes are not "followed" correctly by the body due to the altered expression of the genes, the cells in the brain can no longer function normally, which may contribute to the signs and symptoms of the disease. However, the genes themselves are not changed in such a way that these changes are passed down to an individual's children.

Prevention

Treating liver disorders may prevent some cases of hepatic encephalopathy. Avoiding heavy drinking and intravenous drug use can prevent many liver disorders.

If there are any nervous system symptoms in a person with known or suspected liver disease, call for immediate medical attention.

Diagnosis

Investigations

The diagnosis of hepatic encephalopathy can only be made in the presence of confirmed liver disease (types A and C) or a portosystemic shunt (type B), as its symptoms are similar to those encountered in other encephalopathies. To make the distinction, abnormal liver function tests and/or ultrasound suggesting liver disease are required, and ideally liver biopsy. The symptoms of hepatic encephalopathy may also arise from other conditions, such as cerebral haemorrhage and seizures (both of which are more common in chronic liver disease). A CT scan of the brain may be required to exclude haemorrhage, and if seizure activity is suspected an electroencephalograph (EEG) study may be performed. Rarer mimics of encephalopathy are meningitis, encephalitis, Wernicke's encephalopathy and Wilson's disease; these may be suspected on clinical grounds and confirmed with investigations.

The diagnosis of hepatic encephalopathy is a clinical one, once other causes for confusion or coma have been excluded; no test fully diagnoses or excludes it. Serum ammonia levels are elevated in 90% of patients, but not all hyperammonaemia (high ammonia levels) is associated with encephalopathy. A CT scan of the brain usually shows no abnormality except in stage IV encephalopathy, when cerebral oedema may be visible. Other neuroimaging modalities, such as magnetic resonance imaging (MRI), are not currently regarded as useful, although they may show abnormalities. Electroencephalography shows no clear abnormalities in stage 0, even if minimal HE is present; in stages I, II and III there are triphasic waves over the frontal lobes that oscillate at 5 Hz, and in stage IV there is slow delta wave activity. However, the changes in EEG are not typical enough to be useful in distinguishing hepatic encephalopathy from other conditions.

Once the diagnosis of encephalopathy has been made, efforts are made to exclude underlying causes (such as listed above in "causes"). This requires blood tests (urea and electrolytes, full blood count, liver function tests), usually a chest X-ray, and urinalysis. If there is ascites, diagnostic paracentesis (removal of a fluid sample with a needle) may be required to identify spontaneous bacterial peritonitis (SBP).

Minimal hepatic encephalopathy

The diagnosis of minimal hepatic encephalopathy requires neuropsychological testing by definition. Older tests include the "numbers connecting test" A and B (measuring the speed at which one could connect randomly dispersed numbers 1–20), the "block design test" and the "digit-symbol test". In 2009 an expert panel concluded that neuropsychological test batteries aimed at measuring multiple domains of cognitive function are generally more reliable than single tests, and tend to be more strongly correlated with functional status. Both the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and PSE-Syndrom-Test may be used for this purpose. The PSE-Syndrom-Test, developed in Germany and validated in several other European countries, incorporates older assessment tools such as the number connection test.

Prognosis

Acute hepatic encephalopathy may be treatable. Chronic forms of the disorder often keep getting worse or continue to come back.

Both forms may result in irreversible coma and death. Approximately 80% (8 out of 10 patients) die if they go into a coma. Recovery and the risk of the condition returning vary from patient to patient.

Treatment

Those with severe encephalopathy (stages 3 and 4) are at risk of obstructing their airway due to decreased protective reflexes such as the gag reflex. This can lead to respiratory arrest. Transferring the patient to a higher level of nursing care, such as an intensive care unit, is required and intubation of the airway is often necessary to prevent life-threatening complications (e.g., aspiration or respiratory failure). Placement of a nasogastric tube permits the safe administration of nutrients and medication.

The treatment of hepatic encephalopathy depends on the suspected underlying cause (types A, B or C) and the presence or absence of underlying causes. If encephalopathy develops in acute liver failure (type A), even in a mild form (grade 1–2), it indicates that a liver transplant may be required, and transfer to a specialist centre is advised. Hepatic encephalopathy type B may arise in those who have undergone a TIPSS procedure; in most cases this resolves spontaneously or with the medical treatments discussed below, but in a small proportion of about 5%, occlusion of the shunt is required to address the symptoms.

In hepatic encephalopathy type C, the identification and treatment of alternative or underlying causes is central to the initial management. Given the frequency of infection as the underlying cause, antibiotics are often administered empirically (without knowledge of the exact source and nature of the infection). Once an episode of encephalopathy has been effectively treated, a decision may need to be made on whether to prepare for a liver transplant.

Diet
In the past, it was thought that consumption of protein even at normal levels increased the risk of hepatic encephalopathy. This has been shown to be incorrect. Furthermore, many people with chronic liver disease are malnourished and require adequate protein to maintain a stable body weight. A diet with adequate protein and energy is therefore recommended.

Dietary supplementation with Branched-chain amino acids has shown improvement of encephalopathy and other complications of cirrhosis.Some studies have shown benefit of administration of probiotics ("healthy bacteria").

Lactulose/lactitol
Lactulose and lactitol are disaccharides that are not absorbed from the digestive tract. They are thought to decrease the generation of ammonia by bacteria, render the ammonia inabsorbable by converting it to ammonium (NH4+) ions, and increase transit of bowel content through the gut. Doses of 15-30 ml are administered three times a day; the result is aimed to be 3–5 soft stools a day, or (in some settings) a stool pH of <6.0. Lactulose may also be given by enema, especially if encephalopathy is severe. More commonly, phosphate enemas are used. This may relieve constipation, one of the causes of encephalopathy, and increase bowel transit.

A 2004 review by the Cochrane Collaboration concluded that there was insufficient evidence to determine whether lactulose and lactitol are of benefit for hepatic encephalopathy, but it remains the first-line treatment for type C hepatic encephalopathy. In acute liver failure, it is unclear whether lactulose is beneficial. Furthermore, it may lead to bloating and as such interfere with a liver transplant procedure if required.

Antibiotics
The antibiotics neomycin and metronidazole were previously used as a treatment for hepatic encephalopathy. The rationale of their use was the fact that ammonia and other waste products are generated and converted by intestinal bacteria, and killing these bacteria would reduce the generation of these waste products. Neomycin was chosen because of its low intestinal absorption, as neomycin and similar aminoglycoside antibiotics may cause hearing loss and renal failure if used parenterally. Later studies showed that neomycin was indeed absorbed enterally, with resultant complications. Metronidazole, similarly, was abandoned because prolonged use could cause peripheral neuropathy (nerve damage), in addition to gastrointestinal side effects.

Rifaximin ( Normix) - has been approved for the indication: Reduction in the risk of over hepatic encephalopathy (HE) recurrence in patients greater than or equal to 18 years of age

LOLA
A preparation of L-ornithine and L-aspartate (LOLA) is used to increase the generation of urea through the urea cycle, a metabolic pathway that removes ammonia by turning it into the neutral substance urea. It may be combined with lactulose and/or rifaximin (Normix) if these alone are ineffective at controlling symptoms.

 

Resources

Refer to Research Publications.