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. 2010 Jul;30(7):1384-93.
doi: 10.1038/jcbfm.2010.22. Epub 2010 Mar 10.

Blood-brain barrier permeability for ammonia in patients with different grades of liver fibrosis is not different from healthy controls

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Blood-brain barrier permeability for ammonia in patients with different grades of liver fibrosis is not different from healthy controls

Annemarie Goldbecker et al. J Cereb Blood Flow Metab. 2010 Jul.

Abstract

Increased blood-brain barrier (BBB) permeability for ammonia is considered to be an integral part of the pathophysiology of hepatic encephalopathy (HE) in patients with liver cirrhosis. Increased glutamate-/glutamine-signal intensity in magnetic resonance spectroscopic studies of the brain in cirrhotic patients was explained as a consequence of increased cerebral ammonia uptake. As similar spectroscopic alterations are present in patients with liver fibrosis, we hypothesized that BBB permeability for ammonia is already increased in liver fibrosis, and thereby contributing to the development of HE. To test this hypothesis, cerebral perfusion and ammonia metabolism were examined through positron emission tomography with (15)O-water, respectively, (13)N-ammonia in patients with Ishak grades 2 and 4 fibrosis, cirrhosis, and healthy controls. There were neither global nor regional differences of cerebral blood flow, the rate constant of unidirectional transport of ammonia from blood into brain tissue, the permeability surface area product of the BBB for ammonia, the net metabolic clearance rate constant of ammonia from blood into glutamine in brain, or the metabolic rate of ammonia. The hypothesis that increased permeability of the BBB for ammonia in patients with liver fibrosis contributes to the later development of HE could not be supported by this study.

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Figures

Figure 1
Figure 1
Model of cerebral ammonia metabolism.
Figure 2
Figure 2
Whole brain VOI for assessment of ‘global' parameters obtained by the union of the 15 standard VOIs (see text) predefined in template space by the automated anatomic labeling (AAL) atlas made available by Tzourio-Mazoyer et al (2002). Shown is a transversal slice of the whole brain VOI (left) and the corresponding slice of the single subject T1 template of SPM2 (right), with corresponding cross-hairs.
Figure 3
Figure 3
15O-water TACs in one representative subject (Ishak score 2). The upper part of the figure shows the delay corrected 15O-water activity in blood (input function), the TAC in the whole brain VOI, and the fit by the flow and dispersion model. The lower part of the figure shows the residuals of the fit (note the different scaling of the y axis, the residuals are of the order of 1%). The perfusion was estimated to 0.291 mL/mL/min (coefficient of variance 2.5%). 13N-ammonia TACs of this subject are shown in Figure 4.
Figure 4
Figure 4
13N-ammonia TACs in one representative subject (Ishak score 2, the same subject as in Figure 3). In (A), the time curve of total activity in blood (used for estimation of fbv), the time curve of 13N-ammonia in blood (input function) obtained by population-based metabolite correction from the total blood activity, the TAC in the whole brain VOI, the fit by the irreversible two-tissue compartment model, and the residuals of the fit were shown. Model estimates in this case were delay=3.3 secs (coefficient of variance 12.9%), fbv=3.6% (3.5%), K1=0.158 mL/mL/min (0.6%). In (B), the corresponding Gjedde–Patlak plot that resulted in slope=Kmet=0.115 mL/mL/min (2.2%) and intercept=0.565 mL/mL (19.5%) is shown. The ratio Kmet/K1 was 0.73, and the permeability surface area product PSBBB for ammonia was computed to 0.228 mL/mL/min.

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