Encephalopathy in acute liver failure resulting from acetaminophen intoxication: new observations with potential therapy

Abstract

Objective: Hyperammonemia is a major contributing factor to the encephalopathy associated with liver disease. It is now generally accepted that hyperammonemia leads to toxic levels of glutamine in astrocytes. However, the mechanism by which excessive glutamine is toxic to astrocytes is controversial. Nevertheless, there is strong evidence that glutamine-induced osmotic swelling, especially in acute liver failure, is a contributing factor: the osmotic gliopathy theory. The object of the current communication is to present evidence for the osmotic gliopathy theory in a hyperammonemic patient who overdosed on acetaminophen.

Design: Case report.

Setting: Johns Hopkins Hospital.

Patient: A 22-yr-old woman who, 36 hrs before admission, ingested 15 g acetaminophen was admitted to the Johns Hopkins Hospital. She was treated with N-acetylcysteine. Physical examination was unremarkable; her mental status was within normal limits and remained so until approximately 72 hrs after ingestion when she became confused, irritable, and agitated.

Interventions: She was intubated, ventilated, and placed on lactulose. Shortly thereafter, she was noncommunicative, unresponsive to painful stimuli, and exhibited decerebrate posturing. A clinical diagnosis of cerebral edema and increased intracranial pressure was made. She improved very slowly until 180 hrs after ingestion when she moved all extremities. She woke up shortly thereafter.

Measurements and main results: Despite the fact that hyperammonemia is a major contributing factor to the encephalopathy observed in acute liver failure, the patient's plasma ammonia peaked when she exhibited no obvious neurologic deficit. Thereafter, her plasma ammonia decreased precipitously in parallel with a worsening neurologic status. She was deeply encephalopathic during a period when her liver function and plasma ammonia had normalized. Plasma glutamine levels in this patient were high but began to normalize several hours after plasma ammonia had returned to normal. The patient only started to recover as her plasma glutamine began to return to normal.

Conclusions: We suggest that the biochemical data are consistent with the osmotic gliopathy theory--high plasma ammonia leads to high plasma glutamine--an indicator of excess glutamine in astrocytes (the site of brain glutamine synthesis). This excess glutamine leads to osmotic stress in these cells. The lag in recovery of brain function presumably reflects time taken for the astrocyte glutamine concentration to return to normal. We hypothesize that an inhibitor of brain glutamine synthesis may be an effective treatment modality for acute liver failure.

Fig. 1

Relationship among coma score (yellow triangles), liver function (as assessed by plasma AST; green stars) and plasma biochemistries (NH₄ ⁺, blue squares; glutamine, red circles). The zero time (pre-ingestion) values of plasma ammonia, glutamine, AST and coma score were assigned normal reference values. Ammonia was measured in the hospital laboratory using the glutamate dehydrogenase method in the Dupont Automatic Clinical Analyzer. The coma scores (Glasgow scale) were measured by the attending nurse. Plasma glutamine was measured by automated amino acid chromatography. AST, aspartate transaminase (aminotransferase) activity. Note that the plasma glutamine was not measured prior to 102 hours. Plasma glutamine probably reached its maximum value coincident with or several hours later than the maximum plasma ammonia level.