Fatigue, depression, and complaints of mild cognitive impairment, such as poor concentration and forgetfulness, are the commonest symptoms reported by patients with chronic hepatitis C virus (HCV) infection.¹ Yet there remains considerable debate as to whether theses symptoms are caused by the virus itself. Fatigue is a multidimensional symptom with multiple, sometimes coexisting, determinants which may be biological, psychological, or sociological. It is an important cause of impaired health related quality of life (HRQL) in HCV infection.² Numerous surveys have documented high prevalences of fatigue but consistently show no relationship with the degree of liver fibrosis, markers of inflammation, or viral load.³ This has led to the conclusion that there is no causal relationship between HCV and neuropsychological symptoms.⁴ Rather, psychological processes associated with diagnostic labelling, social functioning, anxiety about treatment, substance abuse, and depression have been invoked to account for impairments in HRQL.^5,6 In contrast, a number of neuroimaging studies, including a single photon emission computerised tomography (SPECT) study published in this issue by Weissenborn and colleagues,⁷ have suggested that measurable abnormalities exist within the central nervous system (CNS) in a proportion of HCV infected individuals (see page 1624).^8,9,10,11

The issue has tended to become polarised between functional and biological arguments, and the likely interaction between physical and psychological factors has been relatively ignored. Attempts have been made to control for relevant confounding factors to determine whether CNS dysfunction relates directly to HCV infection. In a carefully executed study where 300 HCV infected patients were screened for potential risk factors for cognitive impairment such as cirrhosis, psychiatric comorbidity, or previous substance abuse, a highly selected cohort of …