For some time, it has been known that hepatic encephalopathy is associated with increased activity of the inhibitory transmitter GABA in the cerebral cortex. It has also been observed that increased gabanergic neurotransmission may result from substances that inhibit the binding of endogenous benzodiazepine-like compounds to their receptors (Basile et al). Furthermore, these antagonists are found to have some clinical effect—transient arousal in patients with hepatic encephalopathy. The actions of benzodiazepines are mediated by these receptors; hence the designation GABA-benzodiazepine theory. The practicality of using benzodiazepine receptor antagonists, which are short-acting and reversible (e.g., flumazenil) in the treatment of hepatic encephalopathy, remains to be determined (see Mullen), but they offer an interesting diagnostic test.
Until recently, the ammonia and the gabanergic-benzodiazepine hypotheses of the pathogenesis of hepatic encephalopathy had appeared to be unrelated. However, there is evidence, reviewed by Jones and Basile, that ammonia, even in the modestly elevated concentrations that occur in liver failure, inhibits metabolism of GABA by the astrocytes and enhances gabanergic neurotransmission—a concept that unifies hyperammonemia and the neurotransmitter change. Furthermore, the aforementioned glial abnormality may be the explanation for the disorder of the blood-brain barrier that leads to the brain swelling that is seen in some rapidly developing cases of portal-systemic encephalopathy, the prototype for which is the now infrequent Reye syndrome. A parallel astrocytic dysfunction may lead to disruption of the blood–brain barrier and the brain swelling that is known to occur in cases of acute liver failure.
Despite the incompleteness of our understanding of the role of disordered ammonia metabolism in the genesis of hepatic coma, an awareness of this relationship has provided the few effective means of treating this disorder: restriction of dietary protein; reduction of bowel flora by oral administration of neomycin or kanamycin, which suppresses the urease-producing organisms in the bowel; and the use of enemas. The mainstay of treatment has been oral lactulose, an inert sugar that is metabolized by colonic bacteria that produce hydrogen ions and shifts ammonia to ammonium, a nontoxic product that is eliminated in the stool. The past use of oral neomycin carried a risk of renal damage and ototoxicity and has therefore been replaced by rifaximin, a minimally absorbed antibiotic that has less risk. This antibiotic has also been shown by Bass and coworkers to be highly effective in preventing episodic hepatic encephalopathy in tenuously compensated patients. The salutary effect of these therapeutic measures, the common attribute of which is the lowering of the blood NH3, further supports the theory of ammonia intoxication. Ultimately, in cases of intractable liver failure, transplantation becomes a treatment of last resort.
Other treatments with lesser value include bromocriptine, the aforementioned diazepine antagonist flumazenil, and keto analogues of essential amino acids. Theoretically, the keto analogues should provide a nitrogen-free source of essential amino acids (Maddrey et al), a treatment that has been largely abandoned, and bromocriptine, a dopamine agonist, should enhance dopaminergic transmission (Morgan et al) but its mechanism is not known. Administration of branched-chain amino acids may result in improvement in mental status but their effects have been variable and associated with an increased mortality (Naylor et al). The transient beneficial effect of the benzodiazepine antagonist flumazenil has already been mentioned; it is used as well as a diagnostic test.