Towards more individualised management of hepatitis C virus patients with initially or persistently normal alanineaminotrasferase levels.

Many patients with chronic HCV infection have elevated or fluctuating levels of serum alanine aminotransferase (ALT) and most, if not all of them, have histologic evidence of chronic hepatitis with more or less active inflammation and fibrosis in the liver. The presence of elevated ALT and also the entity of the ALT abnormality have been considered important in the decision to take a liver biopsy and/or to initiate antiviral therapy in hepatitis C, based on the demonstration that there is an evident, although not absolute, correlation between ALT levels and liver disease activity and progression [1], [2], [3] and [4]. On the other hand, chronic HCV infection may also present with normal or minimally elevated ALT in the presence of continuing HCV replication (HCV-RNA positive patients with normal ALT). This subgroup of HCV patients is consistent, representing in most published series around 20–40% of chronically infected patients [5], [6], [7] and [8]. There has been and there is still a continuing debate about the best way to describe and diagnose the condition of ‘chronic HCV infection with normal ALT’ [9] and [10]. Many patients maintain persistently normal ALT levels over a long-term follow-up but a significant subgroup shows biochemical reactivation over time [11], [12] and [13]. Another point of debate centres on the type of underlying liver damage that might be present in these cases despite ALT normality and on the necessity for taking a liver biopsy to identify those cases that might have progressive liver disease and an indication for immediate therapy. Many studies have indeed provided evidence that although the majority of the HCV patients with normal ALT have minimal liver damage, a subgroup may have active and progressive liver disease that is difficult to predict on the basis of the clinical or biochemical parameters only [9] and [13]. Accordingly, recent guidelines and management recommendations indicate that viremic patients with normal ALT should not be considered to be ‘healthy carriers’ [14], [15] and [16]. Also the definition, largely used in the past, of ‘asymptomatic HCV carriers’ seems inappropriate, as evidence is accumulating that impairment of quality of life in chronic HCV infection is largely independent of ALT serum levels [17] and [18]. On the basis of these concepts, the indication for antiviral therapy in this category of HCV patients has received increasing consideration and credit in recent years, and has been further reinforced by the most recent results of a large International clinical trial indicating that pegylated interferon plus Ribavirin combination therapy is effective and safe in these patients [19]. This review will focus on the new emerging concepts about HCV patients with normal ALT as to definition and diagnosis, natural history and optimised management. Recent data on the efficacy and safety of antiviral therapy in this group will also be reviewed.