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Approximately 30% of patients with chronic HCV infection have persistently normal ALT levels. Although formerly referred to as 'healthy' or 'asymptomatic' HCV carriers, and thus historically excluded from antiviral treatment, it has now become clear that the majority of these patients have some degree of histological liver damage that may be significant in up to 20% of cases and might progress towards a more severe degree of liver fibrosis. A significant proportion of patients experience periods of increased serum ALT associated with enhanced disease progression. However, controversies still exist in clinical practice regarding the definition of 'persistent' ALT normality, the virological and histological features of these subjects, the need for liver biopsy, the role of noninvasive tools for the assessment of liver fibrosis, the natural history and the usefulness of antiviral treatment. The advent of new therapeutic options (pegylated interferon plus ribavirin) has shifted treatment targets towards the eradication of underlying infection, with therapy decision based on age, severity of disease and likelihood of response rather than on aminotransferase levels. This review is aimed at approaching the main unresolved issues on this topic, trying to give evidence-based answers to the more frequently asked questions from patients and their physicians., (© 2011 Blackwell Publishing Ltd.)

Approximately 30% of patients with chronic HCV infection show persistently normal ALT levels. Although formerly referred to as 'healthy' or 'asymptomatic' HCV carriers, and thus historically excluded from antiviral treatment, it has now become clear that the majority of these patients have some degree of histological liver damage that may be significant in up to 20% of patients and might progress toward a more severe degree of liver fibrosis. A significant proportion of patients (> or =20%) experience periods of increased serum ALT (flare) associated with enhanced disease progression. However, controversies still exist in clinical practice regarding the definition of 'persistent' ALT normality, the virological and histological features of these subjects, the need for liver biopsy, the role of non invasive tools for the assessment of liver fibrosis (transient hepatic elastography, fibroscan), and the natural history and optimal management of chronic hepatitis C with normal ALT. The advent of new therapeutic options (pegylated interferons plus ribavirin) has shifted treatment targets toward eradication of underlying infection, with therapy decision based on age, severity of disease and likelihood of response rather than on aminotransferase levels. This review does approach the main unresolved issues on this topic in the form of a dialog between a hepatologist and a patient with HCV infection but normal alanine aminotransferase levels, trying to give evidence-based answers to the more frequently asked questions from patients and their physicians., (Copyright 2009 Elsevier B.V. All rights reserved.)

Background/aims: To evaluate, in clinical practice, the efficacy and safety of combined antiviral treatment in hepatitis C virus (HCV) carriers with normal alanine aminotransferase (ALT) levels., Methods: Eighty-eight HCV carriers with persistently normal ALT levels were enrolled. All patients received peginterferon (PEG-IFN) alpha-2a 180 microg once weekly plus ribavirin (RBV) 800 mg/day for 24 weeks (HCV-2 and -3) or 1000-1200 mg/day for 48 weeks (HCV-1)., Results: Rapid virological response (RVR) was seen in 66/88 patients (75%): 19/32 HCV-1 (59%), 40/46 HCV-2 (87%) and 7/10 HCV-3 patients. Younger patients, leaner subjects and patients with non-1 genotype or lower baseline HCV RNA levels were more likely to achieve an RVR. Sustained virological response (SVR) was seen in 69/88 patients (78%): 20/32 HCV-1 patients (62%), 41/46 HCV-2 patients (89%) and 8/10 (80%) HCV-3 patients. The overall SVR rate was 88% in patients with RVR (58/66) and 50% in those without RVR., Conclusions: The combination of PEG-IFN alpha-2a and RBV produces, in patients with normal ALT, virological response rates that are comparable or even higher than those obtained in patients with elevated ALT levels. Thus, we suggest that in selected cases immediate therapy might be preferred to a 'wait-and-see' policy.

Approximately 30% of patients with chronic HCV infection show persistently normal alanine aminotransferase levels (PNAL). The prevalence of HCV carriers with normal liver seems to be very low (less than 15-20%). Liver disease is usually minimal/mild and fibrosis is generally absent or minimal, although the association of normal alanine aminotransferase (ALT) with cirrhosis or with liver cancer has been reported. In all studies, liver histology was, on average, significantly less severe in subjects with PNAL than with abnormal ALT. Although the majority of data seem to show that HCV carriers with normal ALT have mild and stable disease, with a favourable prognosis, several studies reported a significant progression of fibrosis in approximately 20-30% of the patients with ALT normality, and the development of HCC in some cases has been described, despite persistent ALT normality. Sudden worsening of disease with ALT increase and histological deterioration has been described after up to 15 years of follow-up, in particular in patients harboring genotype 2. As to antiviral treatment, it has been clearly stated that it no longer seems reasonable to affirm that sustained response rates for patients with normal ALT levels are any different than those for patients with elevated ALT levels when the combination of pegylated interferon (IFN) and ribavirin is used. The issue at hand is whether or not patients with mild disease should be treated. There are numerous other factors which impact on this decision, including genotype, histology, patients motivation, symptoms, co-morbid illness, and the age of the patient.