Abstract
In patients with impaired liver function and hepatic encephalopathy (HE), consistent elevations of blood ammonia concentration suggest a crucial role in the pathogenesis of HE. Ammonia and acetate are metabolized in brain both primarily in astrocytes. Here, we used dynamic [11C]acetate PET of the brain to measure the contribution of astrocytes to the previously observed reduction of brain oxidative metabolism in patients with liver cirrhosis and HE, compared to patients with cirrhosis without HE, and to healthy subjects. We used a new kinetic model to estimate uptake from blood to astrocytes and astrocyte metabolism of [11C]acetate. No significant differences of the rate constant of oxidation of [11C]acetate (k3) were found among the three groups of subjects. The net metabolic clearance of [11C]acetate from blood was lower in the group of patients with cirrhosis and HE than in the group of healthy subjects (P < 0.05), which we interpret to be an effect of reduced cerebral blood flow rather than a reflection of low [11C]acetate metabolism. We conclude that the characteristic decline of whole-brain oxidative metabolism in patients with cirrhosis with HE is not due to malfunction of oxidative metabolism in astrocytes. Thus, the observed decline of brain oxidative metabolism implicates changes of neurons and their energy turnover in patients with HE.
Highlights
Hepatic encephalopathy (HE) is a common and recurrent complication of liver cirrhosis
Oxygen delivery to the brain by the circulation did not limit the magnitude of CMRO2, suggesting that the reduction of cerebral blood flow (CBF) is secondary to the reduction of CMRO2 (Iversen et al, 2009; Gjedde et al, 2010)
The disposal of ammonia in the brain takes place mainly via formation of glutamine by glutamine synthetase which is located exclusively in astrocytes. This is the basis for the present hypothesis that the reduction in CMRO2 during cirrhosis with HE reflects reduced oxidative metabolism in astrocytes
Summary
Hepatic encephalopathy (HE) is a common and recurrent complication of liver cirrhosis. Compared to patients with cirrhosis without HE and healthy subjects, patients with cirrhosis and HE type C had low cerebral oxygen metabolism (CMRO2) and cerebral blood flow (CBF) in inverse proportion to arterial blood ammonia concentration (Iversen et al, 2009; Dam et al, 2013) Both variables rise to normal after recovery from HE (Dam et al, 2013), indicating that low values of CMRO2 and CBF during HE are related to the encephalopathy rather than to the cirrhosis. The disposal of ammonia in the brain takes place mainly via formation of glutamine by glutamine synthetase which is located exclusively in astrocytes This is the basis for the present hypothesis that the reduction in CMRO2 during cirrhosis with HE reflects reduced oxidative metabolism in astrocytes
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