Focus
Authors: Daniel Shouval
Journal: Journal of Hepatology (2009)

The majority of acutely infected HCV patients develop persistent viral infection with variable necro-inflammatory activity and fibrosis. It is not fully understood why a subset of patients will follow a benign course which may last for decades, and that is characterized by minimal hepatocellular injury and fibrosis while others follow a progressive pass with repeated cycles of hepatocyte injury and fibrosis. In this issue of the Journal, Claassen and co-workers suggest that in patients with chronic hepatitis C, intra-hepatic regulatory T cells play a role in the control and prevention of fibrogenesis. Indeed, it is known that regulatory T cells (Tregs) can induce and maintain antigen-specific immune tolerance. On the other hand, dysfunction of Tregs has been linked to the pathogenesis of a number of immune-mediated disorders suggesting that enhancement of Tregs activity could be considered as a therapeutic mean for control of local inflammatory reactions. The authors describe an inverse correlation between the number of CD4+FoxP3+ Tregs and the degree of fibrosis in liver biopsies from patients chronically infected with HCV. No correlation could be established between Tregs activity and viral load or ALT elevation. The data support a potential role for Tregs in immune control of HCV induced hepatic fibrosis. However, the exact mechanism of how intrahepatic CD4FoxP3+ Tregs limit fibrogenesis remains to be deciphered. During the course of chronic hepatitis B virus infection (CHB), patients frequently undergo periods of exacerbation of hepatocellular injury which sometimes may lead to liver failure. Such flares may occur spontaneously, after withdrawal of anti-viral therapy or following treatment with chemotherapeutic or immune suppressive agents. Historically, the pathogenesis of hepatic flares in CHB was linked to immune activation and quantitative recovery of HBV specific T cells. In this issue of the Journal, Tan et al. challenge this concept through comprehensive studies of the kinetics of innate and adaptive immune responses followed for 10 months in CHB patients who discontinued anti-viral therapy with Adefovir. Control groups (tested non-sequentially) included patients with acute hepatitis B, stable patients with persistent HBV infection, as well as healthy subjects. The results suggest that the increase in HBV replication that precedes flares occurs without innate immune activation except for the increase of serum CXCR-8. Furthermore, hepatic flares were associated with high interferon-gamma inducible chemokine levels including CXCL-9/10, both of which displayed different in vitro requirements for activation between patients with acute or chronic HBV. In the absence of increased circulating T and NK cells during flares, the data suggest different mechanism(s) for the activation of immune induced liver injury in chronic HBV patients with hepatic flares as compared to patients with acute HBV. Overt and occult cognitive and psychomotor deficits have repeatedly been studied in adult patients with cirrhosis and hepatic encephalopathy but little is known about this in children with non-cirrhotic portal hypertension, which is relatively common in East-Asia (15–25% of all cases with portal hypertension). Furthermore, assessment of such deficits in hepatic encephalopathy in general and especially in minimal hepatic encephalopathy (MHE) is inaccurate. In this issue of the Journal, Yadav and co-workers have used a large battery of neurophysiologic and neuropsychological tests to assess the presence of MHE in 22 children from India of whom one third were found to have low-grade cerebral oedema, associated with hyper-ammonemia and decline in cognitive functions. This report is of particular importance for paediatricians, parents and teachers of children with portal vein obstruction and non-cirrhotic portal hypertension. The methodology used for the assessment of neuro-cognitive functions is extensive but also time consuming and costly. Yet, detection of deficits which include among others decreased attention, mental speed, working memory and visual motor skills may be of significance to parents and educators alike. As indicated by the investigators, many of these tests require validation not only in India but also in individual geographic regions with different cultural and socio-economic backgrounds.