Brain Region-Selective Mechanisms Contribute to the Progression of Cerebral Alterations in Acute Liver Failure in Rats

[Background and Aims]: Patients with acute liver failure (ALF) often die of intracranial pressure (IP) and cerebral herniation. Main contributors to increased IP are ammonia, glutamine, edema, and blood flow. The sequence of events and underlying mechanisms, as well as the temporal pattern, regional distribution, and contribution of each parameter to the progression of neurologic deterioration and IP, are unclear. We studied rats with ALF to follow the progression of changes in ammonia, glutamine, grade and type (vasogenic or cytotoxic) of edema, blood-brain barrier permeability, cerebral blood flow, and IP. We assessed whether the changes in these parameters were similar between frontal cortex and cerebellum and evaluated the presence, type, and progression of edema in 12 brain areas. [Methods]: ALF was induced by injection of galactosamine. The grade and type of edema was assessed by measuring the apparent diffusion coefficient by magnetic resonance imaging. Cerebral blood flow was measured by magnetic resonance and blood-brain barrier permeability by Evans bluealbumin extravasation. [Results]: Increased IP arises from an early increase of bloodbrain barrier permeability in certain areas (including cerebellum but not frontal cortex) followed by vasogenic edema. Ammonia and glutamine then increase progressively, leading to cytotoxic edema in many areas. Alterations in lactate and cerebral blood flow are later events that further increase IP. [Conclusions]: Different mechanisms in specific regions of the brain contribute, with different temporal patterns, to the progression of cerebral alterations and IP in ALF. © 2011 AGA Institute.
Funding Supported by grants from the Ministerio Ciencia e Innovacion (SAF2008-00062 and CSD2008-00005) and from the Consellería Educación (ACOMP-2009-025, PROMETEO-2009-027, and ACOMP2010-220), and from Conselleria Sanitat, Generalitat Valenciana (AP-092/09 and AP-024-08).