Abstract

BACKGROUND: Neurocognitive deficits in children with chronic liver disease (CLD) or congenital porto-systemic shunts (CPSS) are incompletely understood. Understanding the molecular underpinnings by non-invasive means could inform management. Aims To characterize the neurometabolic profile in the grey matter (GM) of children with CLD or CPSS and analyze correlations with neurocognitive and biological results. METHODS: Children aged 8–14 were enrolled if they presented with CLD or CPSS. Short-echo-time (16 ms) using 1H-MRS at 7T in GM dominated medial prefrontal cortex was performed, and neurocognitive testing and routine labs were obtained within 3 months of each other following informed consent. RESULTS: 5 patients (8–14 y) including 4 with CLD (2 girls), 1 with CPSS (1 girl), and 4 controls (10–14 y, 2 girls) underwent 1H-MRS. Causes of CLD: congenital disorder of glycosylation (1), progressive familial intrahepatic cholestasis type-2 (1), portal obliterative venopathy (1), autoimmune hepatitis (1). Mean plasma ammonium in patients was 26 umol/l, mean serum bilirubin was in normal range and mean platelet count was 201 G/L (59–346). The 3 patients with CLD showed scores in average or above average on Total Intellectual Quotient measures (WISC-IV). One of the 3 scored below average on the working memory sub-scale of the WISC-IV (<1, 65 SD), while the intellectual profiles were homogenous and above average for the 2 others patients. One of these 2 scored below average on 6/10 parameters on the Conners Continuous Performance Test, suggesting attention deficit. The other two were in range. The patient with CPSS displayed Total Intellectual Quotient below average (<1, 65 SD on the WISC-IV), with additional deficits (<1, 65 SD) in executive and attentional functioning as well as expressive and receptive language. 1H-MRS results: 13 metabolites were reliably quantified. Figure 1 illustrates the differences between CLD and CPSS: the expected increase of brain glutamine and decrease of brain osmolytes (inositol, taurine, total choline) together with a previously unreported decrease in the neurotransmitters glutamate, GABA and N-acetylaspartate. No statistically significant differences were observed between the CLD patients and controls. CONCLUSIONS: In patients with compensated CLD, there were no significant neurometabolic alterations as assessed by high resolution 1H-MRS. In CPSS, however, neurometabolic changes were clear, and likely related to measurably impaired neurocognitive functioning. Together, these results suggest that in CPSS (type B encephalopathy) the brain is likely exposed to a higher load of neurotoxic substances than in patients who have some degree of portal flow (type C).

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