Overt hepatic encephalopathy is generally taken to refer to a syndrome of neuropsychiatric, neuropsychological and neurological disturbances that may arise as a complication of liver disease, and which is reversible.2 This definition is not entirely consistent with the current state of knowledge, however, as there is growing evidence that the reversibility of the syndrome is not complete.11,,12

A recent consensus statement, published following the World Congress of Gastroenterology in 1998, suggested that hepatic encephalopathy be divided into three main types, with further subdivisions within one of the categories (Table 1).13

View this table:

  • Enlarge table
  •  Proposed nomenclature of hepatic encephalopathy (HE)13
  • Table 1
HE type Nomenclature Subcategory Subdivisions
A Encephalopathy associated with acute liver failure
B Encephalopathy associated with portal-systemic bypass, but no intrinsic hepatocellular disease
C Encephalopathy associated with Episodic HE Precipitated
    cirrhosis and portal hypertension or Persistent HE Spontaneous
    portal-systemic shunts Minimal HE Recurrent

Between 10 and 50% of patients with cirrhosis and/or porto-caval shunts will experience an episode of overt hepatic encephalopathy at some time during their illness, with the prevalence varying across the spectrum of severity of the cirrhosis.14,,15 The true incidence and prevalence of overt hepatic encephalopathy in these patients is difficult to establish, because of the considerable heterogeneity in aetiology and disease severity. It is also difficult to diagnose the more subtle forms of hepatic encephalopathy such as stage 1 (Table 2) and minimal hepatic encephalopathy. The lack of a gold standard for assessing the presence of hepatic encephalopathy means that the incidence of these more minor forms is difficult to ascertain.13

View this table:

  • Enlarge table
  •  The clinical stages of hepatic encephalopathy2,20
  • Table 2
Stage Mental state
1 Mild confusion, euphoria or depression, decreased attention, mental slowing, untidiness, slurred speech, irritability, reversal of sleep pattern, possible asterixis.
2 Drowsiness, lethargy, gross mental slowing, obvious personality changes, inappropriate behaviour, intermittent disorientation, lack of sphincter control, obvious asterixis.
3 Somnolent but rousable, unable to perform mental tasks, persistent disorientation, amnesia, occasional attacks of rage, incoherent speech, pronounced confusion, asterixis probably absent.
4 Coma.

The factors that can precipitate overt hepatic encephalopathy are well recognized, and include an oral protein load, gastrointestinal bleeding, electrolyte imbalance, infection and deteriorating liver function.2,,16

It is unlikely that a single mechanism underlies the whole syndrome of hepatic encephalopathy in all its various forms; a multifactorial pathogenesis is much more likely.17–,20 Current thinking suggests that a combination of chronic low-grade glial oedema17 and potentiation of the effects of gamma amino butyric acid (GABA) on the central nervous system by ammonia may be responsible for many of the symptoms of hepatic encephalopathy.

GABA is the major inhibitory neurotransmitter in the human brain.19 Increased GABA-mediated neurotransmission is known to cause impaired consciousness and psychomotor dysfunction.19 In animal models of hepatic encephalopathy, an increase in GABA-ergic tone has been demonstrated due to both an increase in GABA release and enhanced activation of the GABA-A receptor complex.18 Benzodiazepines can act at the GABA-A receptor complex, and increased concentrations of endogenous benzodiazepines are found in the brain in liver failure.18,21,,22

Ammonia is known to be neurotoxic, but usually at much higher levels than those found in liver failure, and even then it does not produce a syndrome like that seen in hepatic encephalopathy; in fact, it tends to cause neuronal excitation.2,,19 However, at the lower concentrations seen in hepatic encephalopathy, ammonia potentiates the actions of GABA, possibly by enhancing ligand binding to the GABA-A receptor complex.19 It is probably for this reason that some patients with hepatic encephalopathy improve following administration of the GABA-A receptor antagonist flumazenil.20,,23

In addition there is some evidence for involvement of the glutamatergic system in hepatic encephalopathy. Glutamate is the major excitatory neurotransmitter in the human brain, and ammonia reduces its synthesis and down-regulates the glutamate receptor in vitro. This would result in reduced excitatory transmission in the brain.18 The dopaminergic, serotonergic and opioid neurotransmitter systems have also been implicated in the pathogenesis of hepatic encephalopathy, and it is likely that all of them and possibly others are involved in this complex syndrome.2,,18

In fulminant hepatic failure where hepatic encephalopathy develops within 8 weeks of the onset of liver disease,24 autopsy reveals brain oedema and astrocyte swelling.20 In patients with cirrhosis and portal-systemic shunts, the typical finding is the Alzheimer type II astrocyte, which is the pathological hallmark of hepatic encephalopathy.2,,20 They are found in many locations, including the cortex and the lenticular, lateral thalamic, dentate and red nuclei.24 In turn, these abnormal astrocytes have been shown to be produced by ammonia.25 These findings are similar to those in the acquired hepatocerebral degeneration syndrome.26–,29

Recent studies have also shown increased levels of manganese in the basal ganglia and to a lesser extent other areas of the brain,30–,32 but the relevance of these findings is undetermined.

Overt or symptomatic hepatic encephalopathy is traditionally graded into four stages (Table 2). The clinical picture is of a derangement of consciousness accompanied by decreased (or occasionally increased) psychomotor activity that if left untreated progresses through increasing drowsiness, stupor and coma.33 Sleep disturbance is one of the more common early signs and occurs in nearly 50% of cases.34

As the encephalopathy progresses along this path, signs of pyramidal tract dysfunction such as hypertonia, hyperreflexia and extensor plantar responses are common, eventually being replaced by hypotonia as coma develops.2 The familiar sign of asterixis is well described in hepatic encephalopathy, but unfortunately also occurs in other metabolic encephalopathies and is not therefore pathognomonic.20 One of the areas in which hepatic encephalopathy can differ from other metabolic encephalopathies is in the early stages when the psychomotor retardation that occurs can produce a striking Parkinsonian syndrome.2 In one study, these Parkinsonian features were shown to correlate with the degree of T1 hyperintensity seen in the basal ganglia on cerebral magnetic resonance imaging and the changes in choline/creatine ratios in the basal ganglia on cerebral magnetic resonance spectroscopy.35



Connie’s Comments: Check for manganese or other metal toxicity that can harm the liver.