Neuropathological changes in the brain of pigs with acute liver failure

Abstract

Kristiansen, R.G. et al., 2010. Neuropathological changes in the brain of pigs with acute liver failure. Scandinavian journal of gastroenterology, 45(7-8) ABSTRACTObjective. 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.

Brain edema in acute liver failure and chronic liver disease: Similarities and differences

“…Only one study demonstrated morphological changes suggestive of neuronal swelling in ALF (hepatic devascularized) pigs in the frontal cortex, cerebellum and brain stem (Kristiansen et al, 2010). This electron microscopy study suggests for the first time that there are alterations in neuronal morphology (with indications of neuronal cell death) in the context of ALF.…”

“…However, in galactosamine-induced ALF in the rabbit, it was reported that capillary endothelial cells appeared normal, and no evidence of brain extravasation to horseradish peroxidase was observed (Traber et al, 1987), contradicting the anterior data. In another model of ALF, induced by hepatic devascularisation, inconsistent results have also been recorded: in pigs, perivascular and interstitial edema, along with a disruption of the pericytic and astrocytic processes in the frontal cortex, cerebellum and brain stem have been described (Kristiansen et al, 2010), while in rats, capillary endothelial vesicles were increased, but the BBB remained intact (Potvin et al, 1984). Overall, these inconsistencies may be due to differences in the use of animal species, models of ALF (etiology of ALF; toxins/surgical procedures), as well as the time of evaluation of the BBB (temporal resolution), given that evaluations were taken at different stages of HE severity.…”

Blood–brain barrier in acute liver failure

“…Other recent studies have also provided evidence supporting the role of vasogenic edema in ALF (Cauli et al, 2011; Chavarria et al, 2010; Kristiansen et al, 2010; Lv et al, 2010). MRI studies of human patients have also recently confirmed the vasogenic element in brain edema in liver failure (Kale et al, 2006; Rai et al, 2008).…”

Brain edema in acute liver failure: Role of neurosteroids

“…BBB breakdown was also identified in hepatic devascularized pigs [47]. Furthermore, alterations in the expression of BBB tight junctional proteins, such as occludin, claudin-5, zonula occludens 1 and 2, have been demonstrated in an animal model of ALF [48].…”