It is caused by accumulation in the bloodstream of toxic substances that are normally removed by the liver. The diagnosis of hepatic encephalopathy requires the presence of impaired liver function and the exclusion of an alternative explanation for the symptoms. Blood tests (ammonia levels) may assist in the diagnosis. Attacks are often precipitated by an intercurrent problem, such as infection or constipation.¹²

Hepatic encephalopathy is reversible with treatment. This relies on suppressing the production of the toxic substances in the intestine and is most commonly done with the laxative lactulose or with non-absorbable antibiotics. In addition, the treatment of any underlying condition may improve the symptoms. In particular settings, such as acute liver failure, the onset of encephalopathy may indicate the need for a liver transplant.¹³

Signs and 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.¹

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 edema (swelling of the brain tissue) leads to death.¹

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.²

Causes

In a small proportion of cases, the encephalopathy is caused directly by liver failure; this is more likely in acute liver failure. More commonly, especially in chronic liver disease, hepatic encephalopathy is caused or aggravated by an additional cause, and identifying these causes can be important to treat the episode effectively.¹

Hepatic encephalopathy may also occur after the creation of a transjugular intrahepatic portosystemic shunt (TIPSS). This is used in the treatment of refractory ascites, bleeding from oesophageal varices and hepatorenal syndrome.⁵⁶ TIPSS-related encephalopathy occurs in about 30% of cases, with the risk being higher in those with previous episodes of encephalopathy, higher age, female sex and liver disease due to causes other than alcohol.⁴

Classification and grading

West Haven Criteria

The severity of hepatic encephalopathy is graded with the West Haven Criteria; this is based on the level of impairment of autonomy, changes in consciousness, intellectual function, behavior, and the dependence on therapy .¹⁷⁸

• 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 semistupor, but responsive to verbal stimuli; confusion; gross disorientation
• Grade 4 – Coma (unresponsive to verbal or noxious stimuli)

Types

A classification of hepatic encephalopathy was introduced at the World Congress of Gastroenterology 1998 in Vienna. According to this classification, hepatic encephalopathy is subdivided in type A, B and C depending on the underlying cause.⁷

• Type A (=acute) describes hepatic encephalopathy associated with acute liver failure, typically associated with cerebral oedema
• Type B (=bypass) is caused by portal-systemic shunting without associated intrinsic liver disease
• Type C (=cirrhosis) occurs in patients with cirrhosis – this type is subdivided in episodic, persistent and minimal encephalopathy

The term minimal encephalopathy (MHE) is defined as encephalopathy that does not lead to clinically overt cognitive dysfunction, but can be demonstrated with neuropsychological studies.⁷⁹ This is still an important finding, as minimal encephalopathy has been demonstrated to impair quality of life and increase the risk of involvement in road traffic accidents.¹⁰

Pathogenesis

There are various explanations why liver dysfunction or portosystemic shunting might lead to encephalopathy. In healthy subjects, nitrogen-containing compounds from the intestine, generated by gut bacteria from food, are transported by the portal vein to the liver, where 80–90% is metabolised through the urea cycle and/or excreted immediately. This process is impaired in all subtypes of hepatic encephalopathy, either because the hepatocytes (liver cells) are incapable of metabolising the waste products or because portal venous blood bypasses the liver through collateral circulation or a medically constructed shunt. Nitrogenous waste products accumulate in the systemic circulation (hence the older term “portosystemic encephalopathy”). The most important waste product is ammonia (NH₃). This small molecule crosses the blood–brain barrier and is absorbed and metabolised by the astrocytes, a population of cells in the brain that constitutes 30% of the cerebral cortex. Astrocytes use ammonia when synthesising glutamine from glutamate. The increased levels of glutamine lead to an increase in osmotic pressure in the astrocytes, which become swollen. There is increased activity of the inhibitory γ-aminobutyric acid (GABA) system, and the energy supply to other brain cells is decreased. This can be thought of as an example of brain oedema of the “cytotoxic” type.¹¹

Despite numerous studies demonstrating the central role of ammonia, ammonia levels don’t always correlate with the severity of the encephalopathy; it is suspected that this means that more ammonia has already been absorbed into the brain in those with severe symptoms whose serum levels are relatively low.¹² Other waste products implicated in hepatic encephalopathy include mercaptans (substances containing a thiol group), short-chain fatty acids and phenol.²

Numerous other abnormalities have been described in hepatic encephalopathy, although their relative contribution to the disease state is uncertain. Loss of glutamate transporter gene expression (especially EAAT 2) has been attributed to acute liver failure.¹² Benzodiazepine-like compounds have been detected at increased levels as well as abnormalities in the GABA neurotransmission system. An imbalance between aromatic amino acids (phenylalanine, tryptophan and tyrosine) and branched-chain amino acids (leucine, isoleucine and valine) has been described; this would lead to the generation of false neurotransmitters (such octopamine and 2-hydroxyphenethylamine). Dysregulation of the serotonin system, too, has been reported. Depletion of zinc and accumulation of manganese may play a role.¹² Inflammation elsewhere in the body may precipitate encephalopathy through the action of cytokines and bacterial lipopolysaccharide on astrocytes.⁴

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.¹² 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.¹ 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.²⁷

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.¹² A CT scan of the brain usually shows no abnormality except in stage IV encephalopathy, when cerebral oedema may be visible.² Other neuroimaging modalities, such as magnetic resonance imaging (MRI), are not currently regarded as useful, although they may show abnormalities.⁷ 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.¹ However, the changes in EEG are not typical enough to be useful in distinguishing hepatic encephalopathy from other conditions.⁷

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).¹

Minimal HE

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”.⁷ 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)¹³ and PSE-Syndrom-Test¹⁴ may be used for this purpose.⁹ The PSE-Syndrom-Test, developed in Germany and validated in several other European countries, incorporates older assessment tools such as the number connection test.⁷⁹¹⁰¹⁴

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).²³ Placement of a nasogastric tube permits the safe administration of nutrients and medication.¹

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.³ 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.⁴

In hepatic encephalopathy type C, the identification and treatment of alternative or underlying causes is central to the initial management.¹²⁴¹⁰ 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).¹⁴ Once an episode of encephalopathy has been effectively treated, a decision may need to be made on whether to prepare for a liver transplant.¹⁰

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.¹⁴

Dietary supplementation with Branched-chain amino acids has shown improvement of encephalopathy and other complications of cirrhosis.¹⁴ Some studies have shown benefit of administration of probiotics (“healthy bacteria”).⁴

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), 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 <6.0.¹²⁴¹⁰ Lactulose may also be given by enema, especially if encephalopathy is severe.¹⁰ More commonly, phosphate enemas are used. This may relieve constipation, one of the causes of encephalopathy, and increase bowel transit.¹

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,¹⁵ but it remains the first-line treatment for type C hepatic encephalopathy.¹ 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.³

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.¹

A safer and probably more effective antibiotic is rifaximin, a nonabsorbable antibiotic from the rifamycin class. This is thought to work in a similar way, but without the complications attached to neomycin and metronidazole. The use of rifaximin is supported by better evidence than lactulose.¹⁵ Due to the long history and lower cost of lactulose use, rifaximin is only used as a second-line treatment if lactulose is poorly tolerated or not effective. When rifaximin is added to lactulose, the combination of the two may be more effective than each component separately.¹ Rifaximin is more expensive than lactulose, but the cost may be offset by reduced hospital admissions for encephalopathy.¹⁰

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 if these alone are ineffective at controlling symptoms.¹

Epidemiology and prognosis

In those with cirrhosis, the risk of developing hepatic encephalopathy is 20% per year, and at any time about 30–45% of people with cirrhosis exhibit evidence of overt encephalopathy. The prevalence of minimal hepatic encephalopathy detectable on formal neuropsychological testing is 60–80%; this increases the likelihood of developing overt encephalopathy in the future.¹⁰ Once hepatic encephalopathy has developed, the prognosis is determined largely by other markers of liver failure, such as the levels of albumin (a protein produced by the liver), the prothrombin time (a test of coagulation, which relies on proteins produced in the liver), the presence of ascites and the level of bilirubin (a breakdown product of hemoglobin which is conjugated and excreted by the liver). Together with the severity of encephalopathy, these markers have been incorporated into the Child-Pugh score; this score determines the one- and two-year survival and may assist in a decision to offer liver transplantation.⁷

In acute liver failure, the development of severe encephalopathy strongly predicts short-term mortality, and is almost as important as the nature of the underlying cause of the liver failure in determining the prognosis. Historically, widely used criteria for offering liver transplantation, such as King’s College Criteria, are of limited use and recent guidelines discourage excessive reliance on these criteria. The occurrence of hepatic encephalopathy in patients with Wilson’s disease (hereditary copper accumulation) and mushroom poisoning indicates an urgent need for a liver transplant.³

History

The occurrence of disturbed behaviour in people with jaundice may have been described in antiquity by Hippocrates of Cos (ca. 460–370 BCE).¹⁴¹⁶ Celsus and Galen (first and third century respectively) both recognised the condition. Many modern descriptions of the link between liver disease and neuropsychiatric symptoms were made in the eighteenth and nineteenth century; for instance, Giovanni Battista Morgagni (1682–1771) reported in 1761 that it was a progressive condition.¹⁶

In the 1950s, several reports enumerated the numerous abnormalities reported previously, and confirmed the previously enunciated theory that metabolic impairment and portosystemic shunting are the underlying mechanism behind hepatic encephalopathy, and that the nitrogen-rich compounds originate from the intestine.¹⁴¹⁷ Many of these studies were done by Professor Dame Sheila Sherlock (1918–2001), then at the Royal Postgraduate Medical School in London and subsequently at the Royal Free Hospital. The same group investigated protein restriction¹⁶ and neomycin.¹⁸

The West Haven classification was formulated by Prof Harold Conn (1925–2011) and colleagues at Yale University while investigating the therapeutic efficacy of lactulose.⁷⁸¹⁹