According to several reports, HCV may invade CNS, causing neurocognitive disorders [1,11,12]. This fact could explain the significant cerebral changes observed in HCV-positive patients.

In this study, ADC was determined through diffusion MRI to assess early abnormalities in the distribution of water in brain compartments in HCV-positive patients with chronic liver disease and their association with the neuropsychiatric and cognitive challenges especially in those with apparently normal brain structure. Also, whether these changes could occur early in chronic HCV patients.

We found that ADC values were significantly increased in parietal NAWM and thalamus in cirrhotics in comparison to CHC patients and controls. This elevated ADC in the brains of cirrhotic patients in the absence of structural evidence of brain edema goes with what has been reported by previous studies [6,13].

The diffusion of water molecules in the human brain is restricted by the tissue microstructure. An increase in ADC may be caused by either decreased restriction or increased water content [6]. Previous studies demonstrated that these higher ADC values using DWI with monoexponential fitting support the concept that the increased brain water in cirrhosis is mainly extracellular (vasogenic edema) [6]. Thus, DW-MRI studies have countered the traditional astrocytic swelling hypothesis, suggesting increased ADC values in low-grade interstitial brain edema, secondary to chronic HE [14-17].

In this study, ADC values of patients with cirrhosis were positively related with the severity of hepatic encephalopathy (HE); the higher grade, the higher ADC values suggesting that these changes in brain water content support the brain edema hypothesis in the pathogenesis of HE. Thus, the assessment of brain ADC can be used in monitoring patients with hepatic encephalopathy and could help in preventing brain edema. Our results were compatible with previous studies that consistently demonstrated that link between increased cerebral ADC and patients with HE; the degree of brain water diffusivity also correlating with grade of HE [6,14, 18,19].

Theories that explain this phenomenon include increased blood-brain barrier permeability secondary to chronic inflammation and cytokine activation [20]. Reduced membranous glial fibrilliary acidic protein (GFAP) in astrocytes has been previously linked to increase diffusivity in the extracellular space; in addition, it regulates astrocytic permeability [21-23].

The development of neurologic manifestations occurs during episodes of HE is better explained by the presence of mixed edema, consisting of chronic vasogenic edema secondary to cirrhosis and superimposed acute cytotoxic edema secondary to hyperammonemic decompensation which induce astrocyte swellings[16].

In agreement with previous studies, we found no significant difference in ADC values between patients with and without MHE. The explanation for this result may be that low-grade interstitial brain edema would not affect neuronal function as it is located extracellular [6,14,24]. Unlike Sugimoto et al. (2008) demonstrated increased cerebral ADC values can predict brain abnormalities in patients with MHE suggesting that Cerebral DWI was a reliable tool for MHE quantification and could predict the development of overt HE [15].

 In this study, ADC was not changed in CHC patients with neuropsychiatric and cognitive changes compared to patients without these changes and controls. This is revealed that neuropsychiatric and cognitive changes related to HCV infection may not be explained by these brain water (diffusivity) changes despite the presence of proinflammatory cytokines and chronic inflammation of endothelial cells of the blood-brain barrier. Unlike our study, Bladowska et al. (2013) [25] revealed that HCV-positive patients had significantly higher ADC values in both inferior fronto-occipital fasciculi (IFOFs) and the left inferior longitudinal fasciculi (ILF), compared to the control subjects using diffusion tensor imaging that may explain the difference with our study. Forton et al.(2001) [3] reported that neuropsychiatric and cognitive changes in CHC patients may be attributed to changes in brain metabolites suggesting that HCV infects the brain directly, activates microglia via peripherally derived cytokines, or both.

In conclusion, these findings of DW- MRI support the participation of brain water distribution abnormalities among different compartments in the pathogenesis of HE but they may not explain the neurologic manifestations in CHC patients. Thus, further studies using advanced diffusion MR imaging  are required to assess neuronal dysfunction in chronic hepatitis C and to evaluate the extent of reversibility of brain ADC changes in cirrhotic patients after liver transplantation.