Hepatic encephalopathy

HE probably reflects a combination of metabolic encephalopathy, brain atrophy, and/or brain oedema rather than a single clinical entity. The exact mechanisms causing brain dysfunction in patients with liver failure are not well understood.

Ammonia has been implicated as a neurotoxin in the pathogenesis of the disease, as ammonia levels are significantly increased in patients with chronic liver failure.[6] However, a lack of strong correlation between serum ammonia levels and the degree of encephalopathy in individual patients suggests that other factors are also likely to play a part in its development.[7]

For patients with chronic liver disease, precipitating factors may include gastrointestinal bleeding, infection, use of sedatives/tranquilisers, hypokalaemia, alkalosis, increased protein intake, and constipation. The presence of portosystemic shunts facilitates the occurrence of HE and is associated with more severe forms.[2]

Gastrointestinal bleeding and increased protein intake lead to increased ammonia production. Hypokalaemia is often accompanied by the movement of extracellular hydrogen ions into cells to maintain electrical neutrality. The subsequent metabolic alkalosis is thought to promote the conversion of ammonium ions (NH4+), charged particles that do not cross the blood-brain barrier, into un-ionised ammonia (NH3), which can cross the blood-brain barrier, thus promoting the disease. In these patients, precipitating causes should be quickly identified and treated.[8]

HE occurs through a combination of pathophysiological mechanisms. The gut is the primary source of ammonia absorbed into the circulation through the portal venous system. Ammonia is a by-product of colonic bacterial catabolism of nitrogenous sources such as ingested protein and secreted urea nitrogen. It is also produced from glutamine by enterocytes. Impaired liver function leads to impaired ammonia clearance. In addition, cirrhosis leads to portosystemic shunting, which reduces ammonia clearance further.

Hyperammonaemia may alter cerebral concentration of amino acids and thus affect neurotransmitter synthesis.[9] Hyperammonaemia may also lead to increased intracellular astrocyte osmolarity, inducing astrocyte swelling, and rarely leads to increased intracranial pressure.[10] Elevated serum ammonia levels can also alter neuronal electrical activity.[11]

Increased activation of the inhibitory gamma-aminobutyric acid (GABA)-benzodiazepine neurotransmitter system and alterations of glutamatergic function have also been implicated in the pathogenesis of HE.[12]

Patients with decompensated cirrhosis have an altered intestinal microbiome. There is a decrease in the number of beneficial bacteria that produce short-chain fatty acids, and relative overgrowth of potentially pathogenic bacteria, particularly gram-negative bacteria.[13] Intestinal barrier dysfunction in cirrhosis allows translocation of bacterial antigens such as endotoxins, cell wall components, and DNA. These products stimulate the innate immune system, leading to production of pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8, and tumour necrosis factor.[14] Systemic inflammation activates microglia in the brain, producing neuroinflammation. The blood-brain barrier also demonstrates increased permeability in several animal models of acute liver failure, leading to increased exposure to neurotoxic substances.[15]

Guidelines representing the position of both the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver outline a four-factor classification system for HE:[1][2]

1) Underlying disease

Type A: HE associated with acute liver failure
Type B: HE associated predominantly with portosystemic bypass or shunting
Type C: HE associated with cirrhosis

2) Grade of HE manifestations and clinical description (West Haven criteria)

Unimpaired: no encephalopathy at all, no history of HE
Minimal (covert): psychometric or neuropsychological alterations of tests exploring psychomotor speed/executive functions or neurophysiological alterations without clinical evidence of mental change
Grade 1 (covert): trivial lack of awareness, euphoria or anxiety, shortened attention span, impairment of addition or subtraction, altered sleep rhythm
Grade 2 (overt): lethargy or apathy, disorientation for time, obvious personality change, inappropriate behaviour, dyspraxia, asterixis
Grade 3 (overt): somnolence to semi-stupor, responsive to stimuli, confused, gross disorientation, bizarre behaviour
Grade 4 (overt): coma

Patients with grade 3 or 4 HE should also be monitored with the Glasgow coma scale.[2]

3) Time

Episodic HE
Recurrent HE (≥2 episodes within 6 months)
Persistent HE (behavioural alterations that are always present and are interspersed with episodes of overt HE)

4) Existence of precipitating factors; HE is either:

Non-precipitated
Precipitated (can be identified in nearly all bouts of episodic HE type C)

For discussion on the management of type A hepatic encephalopathy, see our topic Acute liver failure.

Pathophysiology

Classification