Neuropathological changes in the brain of pigs with acute liver failure

Abstract

Objective. Cerebral edema is a serious complication of acute liver failure (ALF), which may lead to intracranial hypertension and death. An accepted tenet has been that the blood-brain barrier is intact and that brain edema is primarily caused by a cytotoxic etiology due to hyperammonemia. However, the neuropathological changes in ALF have been poorly studied. Using a well characterized porcine model we aimed to investigate ultrastructural changes in the brain from pigs suffering from ALF. Materials and methods. Sixteen female Norwegian Landrace pigs weighing 27–35 kg were randomised into two groups: ALF (n = 8) and sham operated controls (n = 8). ALF was induced with an end-to-side portacaval shunt followed by ligation of the hepatic arteries. Biopsies were harvested from three different areas of the brain (frontal lobe, cerebellum, and brain stem) following eight hours of ALF and analyzed using electron microscopy. Results. Profound perivascular and interstitial edema were found in all three areas. Disruption of pericytic and astrocytic processes were seen, reflecting breakdown/lesion of the blood-brain barrier in animals suffering from ALF. Furthermore, neurons and axons were edematous and surrounded by vesicles. Severe damage to Purkinje neuron (necrosis) and damaged myelin were seen in the cerebellum and brain stem, respectively. Biopsies from sham operated animals were normal. Conclusions. Our data support the concept that vasogenic brain edema plays an important role in the development of intracranial hypertension in pigs with ALF.

Key Words::

• Acute liver failure
• ammonia
• blood-brain-barrier
• cerebral edema
• hepatic encephalopathy

Acknowledgements

The authors thank Janne Andreassen, Monica Figenschou, Hege Hagerup, Harry Jensen, and Mehrdad Sobkhez for excellent technical support during the experiments. Funding: This work has been funded by the Norwegian Research Council, Helse Nord (Regional Research Council), University Hospital of North Norway, and University of Tromsø.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.