We read with great interest the AASLD Practice Guideline1 on the diagnosis, management and treatment of hepatitis C (HCV). However, we have some concerns about the definition of HCV carriers with normal alanine aminotransferase (ALT) given by Strader et al.1
In this paper, a person is considered to have normal ALT levels when “there have been two or more determinations identified to be in the normal range over 6 or more months.” In our opinion, this definition could be misleading, as this observation period is too short and thus not adequate to discriminate between “true” HCV carriers with persistently normal ALT levels (PNAL) and patients with only transient biochemical remission.
It is known that during the course of HCV infection ALT could fluctuate, with long periods of biochemical remission.2 Thus, it has been suggested that at least two different subsets of HCV carriers exist: patients with wide temporal ALT fluctuations that could be within the normal range for several months or years, and true “biochemically silent” carriers showing persistently normal ALT values.3 It is not known whether these subgroups have different natural history and disease progression.4
In clinical practice, increases in the aminotransferase levels are not uncommon, even at intervals longer than 6 months. Two recent prospective studies5, 6 found that many subjects referred as to HCV carriers with PNAL on the basis of a 6-month observation period did suffer from ALT flares during the follow-up. In our study,5 21% of the patients showed ALT flare-ups during a 34-month follow-up period (range, 24-48 months), and Martinot-Peignoux et al.6 found ALT increase even after 60 months of follow-up, thus proving that even prolonged observation periods might be not adequate to distinguish patients with persistent or transient ALT normality. Thus the observation period should not be shorter than 12–18 months, and ALT determinations should be performed every 2 to 3 months. It is possible that the different degree of liver damage observed in different studies as well as the different prevalence of true “healthy” HCV carriers could be due at least in part to the fact that also patients with transiently normal ALT could have been included in these studies.4
In the light of these data, the Committee for HCV carriers with normal alanine aminotransferase levels of the Italian Association for the Study of the Liver suggested that the definition of HCV carriers with PNAL should be made on the basis of at least 9 normal ALT values 2 months apart over a 18-month period.7
Liver histological activity was found to be significantly more severe among subjects with ALT flares during the follow-up than in those with PNAL.4 Although a comparison between different studies is difficult, the extent of liver damage varied considerably according to the different definitions of normal aminotransferase values, to the varying observation periods, and to the different frequency of the enzyme tests. In particular, the prevalence of severe forms was higher in studies where the period of observation was limited to 6 months, whereas it was lower in the studies with longer observation periods.7
In conclusion, persistently normal ALT level is really a function of the stringency of follow-up and therefore depends on the frequency of ALT determinations. A single normal ALT value may not be representative of the true pattern of ALT levels for a particular patient. Because of the characteristic fluctuating pattern of ALT values in chronic hepatitis C, only more stringent tests (in terms of number and frequency of ALT evaluations) will make it possible to distinguish subjects with persistently normal ALT values from those in temporary biochemical remission. An observation period of 6 months must therefore be considered inadequate, and, more importantly, the definition should not be based on sporadic ALT determination.