HCV carriers with persistently normal aminotransferase levels: normal does not always mean healthy
2003; Elsevier BV; Volume: 38; Issue: 4 Linguagem: Inglês
10.1016/s0168-8278(03)00018-7
ISSN1600-0641
Autores Tópico(s)Hepatitis B Virus Studies
ResumoApproximately 30% of patients with chronic HCV infection show persistently normal ALT levels (PNAL), and another 40% have minimally raised ALT values [1Marcellin P. Lévy S. Erlinger S. Therapy of hepatitis C: patients with normal aminotransferase levels.Hepatology. 1997; 26: 133S-136SCrossref PubMed Scopus (166) Google Scholar, 2Tassopoulos N.C. Treatment in patients with normal ALT levels.J Hepatol. 1999; 31: 193-196Abstract Full Text PDF PubMed Google Scholar, 3Bacon B.R. Treatment of patients with Hepatitis C and normal serum aminotransferase levels.Hepatology. 2002; 36: S179-S184Crossref PubMed Google Scholar]. Although formerly referred to as ‘healthy’ or ‘asymptomatic’ HCV carriers [[4]Puoti C. Castellacci R. Montagnese F. Hepatitis C virus carriers with normal aminotransferase levels: healthy people or true patients?.Dig Liver Dis. 2000; 32: 634-643Abstract Full Text PDF PubMed Google Scholar], it has now become clear that the majority of these patients have some degree of histological liver damage [5Puoti C. Magrini A. Stati T. Rigato P. Montagnese F. Rossi P. et al.Clinical, histological and virological features of Hepatitis C Virus carriers with persistently normal aminotransferase levels.Hepatology. 1997; 26: 1393-1398Crossref PubMed Scopus (219) Google Scholar, 6Alberti A. Morsica G. Chemello L. Cavalletto D. Noventa F. Pontisso P. Hepatitis C. et al.viraemia and liver disease in symptom-free individuals with anti-HCV.Lancet. 1992; 340: 697-698Abstract PubMed Scopus (409) Google Scholar]. Controversies still exist regarding the definition of ‘persistent’ ALT normality, the virological and histological features of these subjects, and the natural history and optimal management of chronic hepatitis C (CHC) with normal ALT. Despite several cross-sectional studies [5Puoti C. Magrini A. Stati T. Rigato P. Montagnese F. Rossi P. et al.Clinical, histological and virological features of Hepatitis C Virus carriers with persistently normal aminotransferase levels.Hepatology. 1997; 26: 1393-1398Crossref PubMed Scopus (219) Google Scholar, 6Alberti A. Morsica G. Chemello L. Cavalletto D. Noventa F. Pontisso P. Hepatitis C. et al.viraemia and liver disease in symptom-free individuals with anti-HCV.Lancet. 1992; 340: 697-698Abstract PubMed Scopus (409) Google Scholar, 7Prieto M. Olaso V. Verdu C. Cordoba J. Gisbert C. Rayon M. et al.Does the healthy hepatitis C virus carrier state really exist? An analysis using polymerase chain reaction.Hepatology. 1995; 22: 413-417PubMed Google Scholar, 8Shakil A.O. Conry-Cantilena C. Alter H.J. Hayashi P. Kleiner D.E. Tedeschi V. et al.Volunteer blood donors with antibody to hepatitis C virus: clinical, biochemical, virologic, and histologic features.Ann Intern Med. 1995; 123: 330-337Crossref PubMed Scopus (274) Google Scholar, 9Jamal M.M. Sony A. Quinn P.G. Wheeler D.E. Arora S. Johnston D.E. Clinical features of hepatitis C-infected patients with persistently normal alanine transaminase levels in the Southwestern United States.Hepatology. 1999; 30: 1307-1311Crossref PubMed Scopus (128) Google Scholar, 10Serfaty L. Chazouillères O. Pawlotski J.M. Andreani T. Pellet C. Poupon R. Interferon alpha therapy in patients with chronic hepatitis C and persistently normal aminotransferase activity.Gastroenterology. 1996; 110: 291-295Abstract Full Text PDF PubMed Scopus (127) Google Scholar], only few papers evaluated through histological follow-ups the outcome of the disease in these subjects [11Martinot-Peignoux M. Boyer N. Cazals-Hatem D. Bach-Nga P. Gervais A. Le Breton A. et al.Perspective study of anti-hepatitis C virus-positive patients with persistently normal serum ALT with or without detectable serum HCV RNA.Hepatology. 2001; 34: 1000-1005Crossref PubMed Scopus (144) Google Scholar, 12Persico M. Persico E. Suozzo R. Conte S. De Seta M. Sasso F.C. et al.Natural history of hepatitis C virus carriers with persistently normal transaminase levels.Gastroenterology. 2000; 118: 760-764Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 13Cividini A. Rebucci C. Silini E. Mondelli M.U. Is the natural history of HCV carriers with normal aminotransferase levels really benign?.Gastroenterology. 2001; 121: 1526-1527Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. In other studies the yearly progression of fibrosis was calculated using mathematical models [9Jamal M.M. Sony A. Quinn P.G. Wheeler D.E. Arora S. Johnston D.E. Clinical features of hepatitis C-infected patients with persistently normal alanine transaminase levels in the Southwestern United States.Hepatology. 1999; 30: 1307-1311Crossref PubMed Scopus (128) Google Scholar, 14Mathurin P. Moussali J. Cadranel J.F. Thibault V. Charlotte F. Dumouchel P. et al.Slow progression rate of fibrosis in hepatitis C virus patients with persistently normal alanine transaminase activity.Hepatology. 1998; 27: 868-872Crossref PubMed Scopus (300) Google Scholar]. In this issue of the Journal, Hui et al. [[15]Hui C.-K. Belaye T. Montegrande K. Wright T.L. A comparison in the progression of liver fibrosis in chronic hepatitis C between persistently normal and elevated transaminase.J Hepatol. 2003; 38: 511-517Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar] give further convincing evidence that HCV carriers with PNAL are less prone to develop fibrosis progression than patients with abnormal ALT, although some patients may have progressive disease. The study design is original, as only patients with F0–F2 fibrosis on initial biopsy entered the study while those with F3–F4 fibrosis were offered treatment. The main finding of this study is that subjects with PNAL and an initial fibrosis of F0/F1 were less likely to develop progression of fibrosis than those with raised ALT levels, while the difference was not significant when patients with baseline F2 fibrosis were compared [[15]Hui C.-K. Belaye T. Montegrande K. Wright T.L. A comparison in the progression of liver fibrosis in chronic hepatitis C between persistently normal and elevated transaminase.J Hepatol. 2003; 38: 511-517Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar]. Despite this paper and other solid investigations, many important issues remain to be fully answered. For example: what is meant by persistent ALT normality? do viral factors (such as viral load, HCV genotypes, quasispecies diversity) or host factors (such as gender, age, host immune response to HCV infected cells, HLA phenotype) differ between HCV carriers with normal or abnormal ALT levels? is histology on average milder in subjects with PNAL than in patients with abnormal ALT? is disease progression slower in patients with PNAL? Is the duration of available histological follow-ups adequate to draw conclusions about the outcome of this particular category of patients? and finally, are routine liver biopsy and antiviral treatment needed in these subjects? The definition of HCV carrier with PNAL should not be merely based upon the persistent normality of aminotransferases [[3]Bacon B.R. Treatment of patients with Hepatitis C and normal serum aminotransferase levels.Hepatology. 2002; 36: S179-S184Crossref PubMed Google Scholar], as it implies the consistent normality of all biochemical and haematological tests, the absence of symptoms or signs of liver disease, and the normality of imaging studies [[16]Puoti C, Guido M, Mangia A, Persico M, Prati D. Italian Study for the Study of the Liver (AISF) ad hoc Committee ‘HCV carriers with persistently normal ALT levels’. On-line final statement. http://www.webaisf.org.Google Scholar]. It is known that during the course of HCV infection ALT levels could fluctuate, with long periods of biochemical remission [1Marcellin P. Lévy S. Erlinger S. Therapy of hepatitis C: patients with normal aminotransferase levels.Hepatology. 1997; 26: 133S-136SCrossref PubMed Scopus (166) Google Scholar, 2Tassopoulos N.C. Treatment in patients with normal ALT levels.J Hepatol. 1999; 31: 193-196Abstract Full Text PDF PubMed Google Scholar, 3Bacon B.R. Treatment of patients with Hepatitis C and normal serum aminotransferase levels.Hepatology. 2002; 36: S179-S184Crossref PubMed Google Scholar]. 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, and true ‘biochemically silent’ carriers, showing persistently normal ALT values [4Puoti C. Castellacci R. Montagnese F. Hepatitis C virus carriers with normal aminotransferase levels: healthy people or true patients?.Dig Liver Dis. 2000; 32: 634-643Abstract Full Text PDF PubMed Google Scholar, 5Puoti C. Magrini A. Stati T. Rigato P. Montagnese F. Rossi P. et al.Clinical, histological and virological features of Hepatitis C Virus carriers with persistently normal aminotransferase levels.Hepatology. 1997; 26: 1393-1398Crossref PubMed Scopus (219) Google Scholar]. It is not known whether these subgroups have different natural history and disease progression [17Puoti C. Castellacci R. Montagnese F. Zaltron S. Stornaiuolo G.F. Bergami N. et al.Histological and virological features and follow-up of Hepatitis C Virus carriers with normal aminotransferase levels: The Italian Prospective Study of The Asymptomatic C Carriers (ISACC).J Hepatol. 2002; 37: 117-123Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 18Hayashi J. Furusyo N. Ariyama I. Sawayiama Y. Etoh Y. Kashiwagi S. A relationship between the evolution of hepatitis C variants, liver damage and hepatocellular carcinoma in patients with Hepatitis C viremia.J Infect Dis. 2000; 181: 1523-1527Crossref PubMed Scopus (71) Google Scholar]. Liver histological activity was found to be significantly more severe among subjects with ALT flares during the follow-up than in those with PNAL [[17]Puoti C. Castellacci R. Montagnese F. Zaltron S. Stornaiuolo G.F. Bergami N. et al.Histological and virological features and follow-up of Hepatitis C Virus carriers with normal aminotransferase levels: The Italian Prospective Study of The Asymptomatic C Carriers (ISACC).J Hepatol. 2002; 37: 117-123Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar]. The 1997 NIH Consensus Development Conference on the management of Hepatitis C [[1]Marcellin P. Lévy S. Erlinger S. Therapy of hepatitis C: patients with normal aminotransferase levels.Hepatology. 1997; 26: 133S-136SCrossref PubMed Scopus (166) Google Scholar] and the EASL International Consensus Conference [[2]Tassopoulos N.C. Treatment in patients with normal ALT levels.J Hepatol. 1999; 31: 193-196Abstract Full Text PDF PubMed Google Scholar] suggested that the definition of HCV carriers with PNAL should be made on the basis of at least three normal ALT values 2 months apart over a 6-month period. However, two recent prospective studies [11Martinot-Peignoux M. Boyer N. Cazals-Hatem D. Bach-Nga P. Gervais A. Le Breton A. et al.Perspective study of anti-hepatitis C virus-positive patients with persistently normal serum ALT with or without detectable serum HCV RNA.Hepatology. 2001; 34: 1000-1005Crossref PubMed Scopus (144) Google Scholar, 17Puoti C. Castellacci R. Montagnese F. Zaltron S. Stornaiuolo G.F. Bergami N. et al.Histological and virological features and follow-up of Hepatitis C Virus carriers with normal aminotransferase levels: The Italian Prospective Study of The Asymptomatic C Carriers (ISACC).J Hepatol. 2002; 37: 117-123Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar] have shown that many subjects referred as to HCV carriers with PNAL on the basis of this definition could have ALT flare-ups during the 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 2–3 months [[16]Puoti C, Guido M, Mangia A, Persico M, Prati D. Italian Study for the Study of the Liver (AISF) ad hoc Committee ‘HCV carriers with persistently normal ALT levels’. On-line final statement. http://www.webaisf.org.Google Scholar]. 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 [[17]Puoti C. Castellacci R. Montagnese F. Zaltron S. Stornaiuolo G.F. Bergami N. et al.Histological and virological features and follow-up of Hepatitis C Virus carriers with normal aminotransferase levels: The Italian Prospective Study of The Asymptomatic C Carriers (ISACC).J Hepatol. 2002; 37: 117-123Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar]. This is perhaps a weakness of the work of Hui et al., in which the patients were followed-up every year. However, the possibility that also patients in transient biochemical remission have been recruited seems to be very low, given the long follow-up of the patients in study. Another important issue regards the range of ALT ‘normality’ and the definition of the upper limit of the normal (ULN) for patients with CHC. The concept of ‘normal’ ALT remains highly arbitrary [[3]Bacon B.R. Treatment of patients with Hepatitis C and normal serum aminotransferase levels.Hepatology. 2002; 36: S179-S184Crossref PubMed Google Scholar] and the precise meaning of ULN has not been defined. Recent studies suggest that normal values currently used in clinical practice might underestimate the frequency of CLD [19Piton A. Poynard T. Imbert-Bismut F. Khalil L. Delattre J. Pelissiere E. et al.Factors associated with serum alanine transaminase activity in healthy subjects: consequences for the definition of normal values, for selection of blood donors, and for patients with chronic hepatitis C.Hepatology. 1998; 27: 1213-1219Crossref PubMed Scopus (275) Google Scholar, 20Prati D. Taioli E. Zanella A. Della Torre E. Butelli S. Del Vecchio E. et al.Updated definitions of healthy ranges for serum alanine aminotransferase.Ann Intern Med. 2002; 137: 1-10Crossref PubMed Scopus (1180) Google Scholar]. Indeed, in CHC ALT levels can be influenced by several other factors, such as alcohol consumption, body weight, gender, age, non-alcoholic fatty liver [20Prati D. Taioli E. Zanella A. Della Torre E. Butelli S. Del Vecchio E. et al.Updated definitions of healthy ranges for serum alanine aminotransferase.Ann Intern Med. 2002; 137: 1-10Crossref PubMed Scopus (1180) Google Scholar, 21Gordon S.C. Fang J.W.S. Silverman A. McHutchinson J.G. Albrecht J.K. The significance of baseline serum alanine aminotransferase on pretreatment disease characteristics and response to antiviral therapy in chronic hepatitis C.Hepatology. 2000; 32: 400-404Crossref PubMed Scopus (70) Google Scholar]. Interestingly, in a study of therapy with interferon (IFN) plus ribavirin of subjects with PNAL [[22]Di Bisceglie A.M. Thompson J. Smith-Wilkaitis N.S. Brunt E.M. Bacon B.R. Combination of interferon and ribavirin in chronic hepatitis C: re-treatment of nonresponders to interferon.Hepatology. 2001; 33: 704-707Crossref PubMed Scopus (109) Google Scholar] it has been found that in sustained responders ALT levels, although already within the normal range before treatment, decreased after treatment to ‘more normal’ values (from a mean of 42 to 19 IU/l). As far as concerns demographic and virological features of HCV carriers with PNAL, the majority of the studies show a clear prevalence of females [5Puoti C. Magrini A. Stati T. Rigato P. Montagnese F. Rossi P. et al.Clinical, histological and virological features of Hepatitis C Virus carriers with persistently normal aminotransferase levels.Hepatology. 1997; 26: 1393-1398Crossref PubMed Scopus (219) Google Scholar, 17Puoti C. Castellacci R. Montagnese F. Zaltron S. Stornaiuolo G.F. Bergami N. et al.Histological and virological features and follow-up of Hepatitis C Virus carriers with normal aminotransferase levels: The Italian Prospective Study of The Asymptomatic C Carriers (ISACC).J Hepatol. 2002; 37: 117-123Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 23Renou C. Halfon P. Pol S. Cacoub P. Jouve E. Bronowicki J.P. et al.Histological features and HLA class II alleles in HCV chronically infected patients with persistently normal alanine aminotransferase levels.Gut. 2002; 51: 585-590Crossref PubMed Scopus (70) Google Scholar], although the clinical significance of this observation has not been yet established. Studies addressing HCV genotype distribution, serum HCV RNA levels and quasispecies diversity showed conflicting results. Several studies from Italy [5Puoti C. Magrini A. Stati T. Rigato P. Montagnese F. Rossi P. et al.Clinical, histological and virological features of Hepatitis C Virus carriers with persistently normal aminotransferase levels.Hepatology. 1997; 26: 1393-1398Crossref PubMed Scopus (219) Google Scholar, 13Cividini A. Rebucci C. Silini E. Mondelli M.U. Is the natural history of HCV carriers with normal aminotransferase levels really benign?.Gastroenterology. 2001; 121: 1526-1527Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 17Puoti C. Castellacci R. Montagnese F. Zaltron S. Stornaiuolo G.F. Bergami N. et al.Histological and virological features and follow-up of Hepatitis C Virus carriers with normal aminotransferase levels: The Italian Prospective Study of The Asymptomatic C Carriers (ISACC).J Hepatol. 2002; 37: 117-123Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 24Silini E. Bono F. Cividini A. Cerino A. Bruno S. Rossi S. et al.Differential distribution of hepatitis C virus genotypes in patients with and without liver function abnormalities.Hepatology. 1995; 21: 285-290PubMed Google Scholar] found that HCV type 2 was more frequent in subjects with PNAL, and genotype 1b in those with abnormal ALT. No association has been found between HCV type and the severity of liver damage [5Puoti C. Magrini A. Stati T. Rigato P. Montagnese F. Rossi P. et al.Clinical, histological and virological features of Hepatitis C Virus carriers with persistently normal aminotransferase levels.Hepatology. 1997; 26: 1393-1398Crossref PubMed Scopus (219) Google Scholar, 25Prati D. Capelli C. Zanella A. Mozzi F. Bosoni P. Pappalettera M. Zanuso F. et al.Influence of different hepatitis C virus genotypes on the course of asymptomatic hepatitis C virus infection.Gastroenterology. 1996; 110: 178-183Abstract Full Text PDF PubMed Scopus (118) Google Scholar], and in the majority of the studies serum HCV RNA titres did not differ between subjects with PNAL and with abnormal ALT [5Puoti C. Magrini A. Stati T. Rigato P. Montagnese F. Rossi P. et al.Clinical, histological and virological features of Hepatitis C Virus carriers with persistently normal aminotransferase levels.Hepatology. 1997; 26: 1393-1398Crossref PubMed Scopus (219) Google Scholar, 8Shakil A.O. Conry-Cantilena C. Alter H.J. Hayashi P. Kleiner D.E. Tedeschi V. et al.Volunteer blood donors with antibody to hepatitis C virus: clinical, biochemical, virologic, and histologic features.Ann Intern Med. 1995; 123: 330-337Crossref PubMed Scopus (274) Google Scholar, 17Puoti C. Castellacci R. Montagnese F. Zaltron S. Stornaiuolo G.F. Bergami N. et al.Histological and virological features and follow-up of Hepatitis C Virus carriers with normal aminotransferase levels: The Italian Prospective Study of The Asymptomatic C Carriers (ISACC).J Hepatol. 2002; 37: 117-123Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar]. Viral heterogeneity has been correlated with the severity and progression of disease in HCV carriers with PNAL with conflicting results [26Brambilla S. Bellati G. Asti M. Lisa A. Candusso M.E. D'Amico M. et al.Dynamics of hypervariable region 1 in hepatitis C infection and correlation with clinical and virological features of liver disease.Hepatology. 1998; 27: 1678-1686Crossref PubMed Scopus (53) Google Scholar, 27Hayashi J. Kishihara Y. Yamaji K. Furusuyo M. Yamamoto T. Pae I. et al.Hepatitis C viral quasi species and liver damage in patients with chronic hepatitis C virus infection.Hepatology. 1997; 25: 697-701Crossref PubMed Scopus (88) Google Scholar]. However, recent evidence would support the initial findings of a positive correlation between genetic diversity in the hypervariable region 1 of HCV and mild liver damage [[28]Curran R. Jameson C.L. Craggs J.K. Grabowska A.M. Thomson B.J. Robins A. Irving W.L. Ball J.K. Evolutionary trends of the first hypervariable region of the hepatitis C virus E2 protein in individuals with differing liver disease severity.J Gen Virol. 2002; 83: 11-23Crossref PubMed Scopus (48) Google Scholar]. Finally, no correlations have been found between the presence and the severity of histological liver damage and serum HCV RNA levels [[29]Puoti C. Stati T. Magrini A. Serum HCV RNA titer does not predict the severity of liver damage in HCV carriers with normal aminotransferase levels.Liver. 1999; 19: 104-109Crossref PubMed Scopus (46) Google Scholar]. As to liver histology, the prevalence of HCV carriers with normal liver (the true ‘healthy’ HCV carriers) seems to be very low (from 0 to 20%) [9Jamal M.M. Sony A. Quinn P.G. Wheeler D.E. Arora S. Johnston D.E. Clinical features of hepatitis C-infected patients with persistently normal alanine transaminase levels in the Southwestern United States.Hepatology. 1999; 30: 1307-1311Crossref PubMed Scopus (128) Google Scholar, 14Mathurin P. Moussali J. Cadranel J.F. Thibault V. Charlotte F. Dumouchel P. et al.Slow progression rate of fibrosis in hepatitis C virus patients with persistently normal alanine transaminase activity.Hepatology. 1998; 27: 868-872Crossref PubMed Scopus (300) Google Scholar, 17Puoti C. Castellacci R. Montagnese F. Zaltron S. Stornaiuolo G.F. Bergami N. et al.Histological and virological features and follow-up of Hepatitis C Virus carriers with normal aminotransferase levels: The Italian Prospective Study of The Asymptomatic C Carriers (ISACC).J Hepatol. 2002; 37: 117-123Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 23Renou C. Halfon P. Pol S. Cacoub P. Jouve E. Bronowicki J.P. et al.Histological features and HLA class II alleles in HCV chronically infected patients with persistently normal alanine aminotransferase levels.Gut. 2002; 51: 585-590Crossref PubMed Scopus (70) Google Scholar]. The majority of patients have some degree of liver damage on liver biopsy. Liver disease is usually minimal/mild and fibrosis is generally absent or minimal [9Jamal M.M. Sony A. Quinn P.G. Wheeler D.E. Arora S. Johnston D.E. Clinical features of hepatitis C-infected patients with persistently normal alanine transaminase levels in the Southwestern United States.Hepatology. 1999; 30: 1307-1311Crossref PubMed Scopus (128) Google Scholar, 14Mathurin P. Moussali J. Cadranel J.F. Thibault V. Charlotte F. Dumouchel P. et al.Slow progression rate of fibrosis in hepatitis C virus patients with persistently normal alanine transaminase activity.Hepatology. 1998; 27: 868-872Crossref PubMed Scopus (300) Google Scholar, 15Hui C.-K. Belaye T. Montegrande K. Wright T.L. A comparison in the progression of liver fibrosis in chronic hepatitis C between persistently normal and elevated transaminase.J Hepatol. 2003; 38: 511-517Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 17Puoti C. Castellacci R. Montagnese F. Zaltron S. Stornaiuolo G.F. Bergami N. et al.Histological and virological features and follow-up of Hepatitis C Virus carriers with normal aminotransferase levels: The Italian Prospective Study of The Asymptomatic C Carriers (ISACC).J Hepatol. 2002; 37: 117-123Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 23Renou C. Halfon P. Pol S. Cacoub P. Jouve E. Bronowicki J.P. et al.Histological features and HLA class II alleles in HCV chronically infected patients with persistently normal alanine aminotransferase levels.Gut. 2002; 51: 585-590Crossref PubMed Scopus (70) Google Scholar], although the association of normal ALT with cirrhosis [5Puoti C. Magrini A. Stati T. Rigato P. Montagnese F. Rossi P. et al.Clinical, histological and virological features of Hepatitis C Virus carriers with persistently normal aminotransferase levels.Hepatology. 1997; 26: 1393-1398Crossref PubMed Scopus (219) Google Scholar, 6Alberti A. Morsica G. Chemello L. Cavalletto D. Noventa F. Pontisso P. Hepatitis C. et al.viraemia and liver disease in symptom-free individuals with anti-HCV.Lancet. 1992; 340: 697-698Abstract PubMed Scopus (409) Google Scholar, 17Puoti C. Castellacci R. Montagnese F. Zaltron S. Stornaiuolo G.F. Bergami N. et al.Histological and virological features and follow-up of Hepatitis C Virus carriers with normal aminotransferase levels: The Italian Prospective Study of The Asymptomatic C Carriers (ISACC).J Hepatol. 2002; 37: 117-123Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar] or with HCC [[13]Cividini A. Rebucci C. Silini E. Mondelli M.U. Is the natural history of HCV carriers with normal aminotransferase levels really benign?.Gastroenterology. 2001; 121: 1526-1527Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar] has been reported. In all studies, liver histology was, on average, significantly less severe in subjects with PNAL than with abnormal ALT. A recent European Collaborative Study [[30]Pradat P. Alberti A. Poynard T. Esteban J.I. Weiland O. Marcellin P. et al.Predictive value of ALT levels for histologic findings in chronic hepatitis C: a European Collaborative Study.Hepatology. 2002; 36: 973-977PubMed Google Scholar] reported that an important proportion of carriers with PNAL had some histological signs of fibrosis, sometimes severe, and in rare cases cirrhosis was found. The natural course of HCV infection in patients with normal ALT levels is actually not well understood, as only few studies exist [11Martinot-Peignoux M. Boyer N. Cazals-Hatem D. Bach-Nga P. Gervais A. Le Breton A. et al.Perspective study of anti-hepatitis C virus-positive patients with persistently normal serum ALT with or without detectable serum HCV RNA.Hepatology. 2001; 34: 1000-1005Crossref PubMed Scopus (144) Google Scholar, 12Persico M. Persico E. Suozzo R. Conte S. De Seta M. Sasso F.C. et al.Natural history of hepatitis C virus carriers with persistently normal transaminase levels.Gastroenterology. 2000; 118: 760-764Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 13Cividini A. Rebucci C. Silini E. Mondelli M.U. Is the natural history of HCV carriers with normal aminotransferase levels really benign?.Gastroenterology. 2001; 121: 1526-1527Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 14Mathurin P. Moussali J. Cadranel J.F. Thibault V. Charlotte F. Dumouchel P. et al.Slow progression rate of fibrosis in hepatitis C virus patients with persistently normal alanine transaminase activity.Hepatology. 1998; 27: 868-872Crossref PubMed Scopus (300) Google Scholar]. In the study of Martinot-Peignoux et al. [[11]Martinot-Peignoux M. Boyer N. Cazals-Hatem D. Bach-Nga P. Gervais A. Le Breton A. et al.Perspective study of anti-hepatitis C virus-positive patients with persistently normal serum ALT with or without detectable serum HCV RNA.Hepatology. 2001; 34: 1000-1005Crossref PubMed Scopus (144) Google Scholar] no significant differences in both activity and fibrosis score were seen at second biopsy performed after a mean follow-up of 3.5 years. Persico et al. [[12]Persico M. Persico E. Suozzo R. Conte S. De Seta M. Sasso F.C. et al.Natural history of hepatitis C virus carriers with persistently normal transaminase levels.Gastroenterology. 2000; 118: 760-764Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar] showed that liver histology after 5 years of follow-up was not changed with respect to that observed at the entry to study. Two studies [9Jamal M.M. Sony A. Quinn P.G. Wheeler D.E. Arora S. Johnston D.E. Clinical features of hepatitis C-infected patients with persistently normal alanine transaminase levels in the Southwestern United States.Hepatology. 1999; 30: 1307-1311Crossref PubMed Scopus (128) Google Scholar, 14Mathurin P. Moussali J. Cadranel J.F. Thibault V. Charlotte F. Dumouchel P. et al.Slow progression rate of fibrosis in hepatitis C virus patients with persistently normal alanine transaminase activity.Hepatology. 1998; 27: 868-872Crossref PubMed Scopus (300) Google Scholar] found that the estimated rate of fibrosis progression was significantly lower in carriers with PNAL than in subjects with abnormal ALT. Spontaneous HCV RNA clearance has been described in 15% of subjects with PNAL after 3–7 years of follow-up [[13]Cividini A. Rebucci C. Silini E. Mondelli M.U. Is the natural history of HCV carriers with normal aminotransferase levels really benign?.Gastroenterology. 2001; 121: 1526-1527Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. Finally, in a large study from Japan, HCC developed in one-third of people with abnormal ALT, in 4% of those with intermittently abnormal ALT and none of the subjects with PNAL [[18]Hayashi J. Furusyo N. Ariyama I. Sawayiama Y. Etoh Y. Kashiwagi S. A relationship between the evolution of hepatitis C variants, liver damage and hepatocellular carcinoma in patients with Hepatitis C viremia.J Infect Dis. 2000; 181: 1523-1527Crossref PubMed Scopus (71) Google Scholar]. These data seem to show that HCV carriers with normal ALT have mild and stable disease, with a favourable prognosis. In the current issue of the Journal, Hui et al. provide new evidence that the outcome of HCV carriers with PNAL is really benign and on average not progressive [[15]Hui C.-K. Belaye T. Montegrande K. Wright T.L. A comparison in the progression of liver fibrosis in chronic hepatitis C between persistently normal and elevated transaminase.J Hepatol. 2003; 38: 511-517Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar]. Severe fibrosis at second biopsy was detected in 5% of patients with PNAL and 24% of those with abnormal ALT values. Interestingly, no patients with PNAL and an initial fibrosis of F0 to F1 developed severe fibrosis. It is noteworthy that the duration of the histological follow-up in the study of Hui is one of the largest thus far published [11Martinot-Peignoux M. Boyer N. Cazals-Hatem D. Bach-Nga P. Gervais A. Le Breton A. et al.Perspective study of anti-hepatitis C virus-positive patients with persistently normal serum ALT with or without detectable serum HCV RNA.Hepatology. 2001; 34: 1000-1005Crossref PubMed Scopus (144) Google Scholar, 12Persico M. Persico E. Suozzo R. Conte S. De Seta M. Sasso F.C. et al.Natural history of hepatitis C virus carriers with persistently normal transaminase levels.Gastroenterology. 2000; 118: 760-764Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 13Cividini A. Rebucci C. Silini E. Mondelli M.U. Is the natural history of HCV carriers with normal aminotransferase levels really benign?.Gastroenterology. 2001; 121: 1526-1527Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]. The reasons for this seemingly benign course of disease are not well understood. It has been suggested an association with a specific genetic background [23Renou C. Halfon P. Pol S. Cacoub P. Jouve E. Bronowicki J.P. et al.Histological features and HLA class II alleles in HCV chronically infected patients with persistently normal alanine aminotransferase levels.Gut. 2002; 51: 585-590Crossref PubMed Scopus (70) Google Scholar, 31Kuzushita N. Hayashi N. Katayama K. Hiramatsu N. Yasumaru M. Murata H. et al.Increased frequency of HLA DR13 in hepatitis C virus carriers with normal ALT levels.J Med Virol. 1996; 48: 1-7Crossref PubMed Scopus (51) Google Scholar] or a weaker immune response to HCV-infected liver cells, with some degree of immune-tolerance [[32]Sangiovanni A. Morales R. Spinzi G.C. Rumi M.G. Casiraghi A. Ceriani R. et al.Interferon alpha treatment of HCV RNA carriers with persistently normal transaminase levels: a pilot randomized controlled study.Hepatology. 1998; 27: 853-856Crossref PubMed Scopus (102) Google Scholar]. However, is the natural history of HCV carriers with PNAL always so benign? Cividini et al. [[13]Cividini A. Rebucci C. Silini E. Mondelli M.U. Is the natural history of HCV carriers with normal aminotransferase levels really benign?.Gastroenterology. 2001; 121: 1526-1527Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar] reported a significant progression of fibrosis (>2 points in score) in 17% of the patients with well-defined ALT normality, and the development in one case of HCC in well-compensated cirrhosis after 5 years of follow-up, 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 [[33]Rumi M.G. De Filippi F. Donato M.F. Del Ninno E. Colombo M. Progressive hepatic fibrosis in healthy carriers of hepatitis C virus with a transaminase breakthrough.J Viral Hepat. 2002; 9: 71-74Crossref PubMed Scopus (40) Google Scholar]. Huy et al. themselves [[15]Hui C.-K. Belaye T. Montegrande K. Wright T.L. A comparison in the progression of liver fibrosis in chronic hepatitis C between persistently normal and elevated transaminase.J Hepatol. 2003; 38: 511-517Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar], although confirming that fibrosis progresses at a slower rate among subjects with PNAL, found at the same time overall fibrosis progression in 22% of the patients with normal ALT. Further, it is very impressive the finding that 5% of the patients with normal ALT in this study developed clinical evidence of cirrhosis during the follow-up. Should patients with CHC and normal ALT undergo antiviral treatment? It might be taken into account that IFN treatment is associated with consistent side effects and reduced quality of life and is not inexpensive, while the risk of progression of the disease in this setting is extremely low. Thus, the cost effectiveness of the treatment in carriers with PNAL is yet to be proven. The 1997 NIH Consensus Conference [[1]Marcellin P. Lévy S. Erlinger S. Therapy of hepatitis C: patients with normal aminotransferase levels.Hepatology. 1997; 26: 133S-136SCrossref PubMed Scopus (166) Google Scholar] and the EASL Consensus Conference [[2]Tassopoulos N.C. Treatment in patients with normal ALT levels.J Hepatol. 1999; 31: 193-196Abstract Full Text PDF PubMed Google Scholar] stated that IFN treatment should not be recommended in these subjects. At the time of that Consensus Conferences only few trials of IFN monotherapy were available [10Serfaty L. Chazouillères O. Pawlotski J.M. Andreani T. Pellet C. Poupon R. Interferon alpha therapy in patients with chronic hepatitis C and persistently normal aminotransferase activity.Gastroenterology. 1996; 110: 291-295Abstract Full Text PDF PubMed Scopus (127) Google Scholar, 32Sangiovanni A. Morales R. Spinzi G.C. Rumi M.G. Casiraghi A. Ceriani R. et al.Interferon alpha treatment of HCV RNA carriers with persistently normal transaminase levels: a pilot randomized controlled study.Hepatology. 1998; 27: 853-856Crossref PubMed Scopus (102) Google Scholar, 34Rossini A. Ravaggi A. Biasi L. Agostinelli E. Bercich L. Gazzola G.B. et al.Virological response to interferon treatment in hepatitis C virus carriers with normal aminotransferase levels and chronic hepatitis.Hepatology. 1997; 26: 1012-1017Crossref PubMed Scopus (45) Google Scholar]. The overall sustained virological response (SVR) in subjects with PNAL was very low (less than 20%) although not different than that observed in patients with abnormal ALT. Further, many patients showed ALT flares during treatment. Given these findings, it was concluded that IFN treatment in subjects with PNAL was not beneficial and may actually worsen the underlying disease [[3]Bacon B.R. Treatment of patients with Hepatitis C and normal serum aminotransferase levels.Hepatology. 2002; 36: S179-S184Crossref PubMed Google Scholar]. In the last few years, treatment of CHC has progressed from IFN monotherapy to IFN plus ribavirin combination therapy, and more recently to PEG-IFN plus ribavirin. Using IFN plus ribavirin therapy for 24 or 48 weeks in patients with persistently normal or with minimally raised ALT levels (less than 1.3–1.5 ULN), SVR rates of 25–50% have been reported [21Gordon S.C. Fang J.W.S. Silverman A. McHutchinson J.G. Albrecht J.K. The significance of baseline serum alanine aminotransferase on pretreatment disease characteristics and response to antiviral therapy in chronic hepatitis C.Hepatology. 2000; 32: 400-404Crossref PubMed Scopus (70) Google Scholar, 22Di Bisceglie A.M. Thompson J. Smith-Wilkaitis N.S. Brunt E.M. Bacon B.R. Combination of interferon and ribavirin in chronic hepatitis C: re-treatment of nonresponders to interferon.Hepatology. 2001; 33: 704-707Crossref PubMed Scopus (109) Google Scholar, 35Lee S.S. Sherman M. Pilot study of interferon-alpha and ribavirin treatment in patients with chronic hepatitis C and normal transaminase values.J Viral Hepat. 2001; 8: 202-205Crossref PubMed Scopus (50) Google Scholar]. The response rates were higher in patients with genotype non-1 and in those treated for 48 weeks [[3]Bacon B.R. Treatment of patients with Hepatitis C and normal serum aminotransferase levels.Hepatology. 2002; 36: S179-S184Crossref PubMed Google Scholar]. More recently, the introduction of the new combination therapy of PEG-IFN plus ribavirin allowed response rates higher than 50%, with a favourable risk-benefit ratio also in patients with benign or slow progressive disease. Although no data in patients with PNAL are yet available, international studies with the new combination therapy in subjects with PNAL are under way. Given the efficacy of the new treatments, which soon became the standard of care for CHC, the 2002 NIH Consensus Development Conference suggested that the issue of whether or not to treat subjects with PNAL should be re-evaluated, and that the issue at hand should be whether or not patients with mild disease should be treated [[3]Bacon B.R. Treatment of patients with Hepatitis C and normal serum aminotransferase levels.Hepatology. 2002; 36: S179-S184Crossref PubMed Google Scholar]. ALT levels may have less importance in deciding who should be treated [[3]Bacon B.R. Treatment of patients with Hepatitis C and normal serum aminotransferase levels.Hepatology. 2002; 36: S179-S184Crossref PubMed Google Scholar]. Many other factors might influence the decision to treat, such as the age of the patient, HCV genotype, liver histology, patients’ motivation, symptoms, extra-hepatic manifestations, and co-morbid illness [[3]Bacon B.R. Treatment of patients with Hepatitis C and normal serum aminotransferase levels.Hepatology. 2002; 36: S179-S184Crossref PubMed Google Scholar]. Finally, should HCV carriers with PNAL undergo routine liver biopsy in clinical practice? In the light of their findings, Hui et al. [[15]Hui C.-K. Belaye T. Montegrande K. Wright T.L. A comparison in the progression of liver fibrosis in chronic hepatitis C between persistently normal and elevated transaminase.J Hepatol. 2003; 38: 511-517Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar] suggest that it may be worthwhile to consider liver biopsy in patients with PNAL in order to stage accurately the fibrosis. However, the role of liver biopsy in these patients is still highly disputed and consensual recommendations are lacking. These uncertainties probably depend on the poor knowledge of the natural history and the lack of solid evidence for the treatment. Experts still differ on whether to biopsy these patients [2Tassopoulos N.C. Treatment in patients with normal ALT levels.J Hepatol. 1999; 31: 193-196Abstract Full Text PDF PubMed Google Scholar, 3Bacon B.R. Treatment of patients with Hepatitis C and normal serum aminotransferase levels.Hepatology. 2002; 36: S179-S184Crossref PubMed Google Scholar, 5Puoti C. Magrini A. Stati T. Rigato P. Montagnese F. Rossi P. et al.Clinical, histological and virological features of Hepatitis C Virus carriers with persistently normal aminotransferase levels.Hepatology. 1997; 26: 1393-1398Crossref PubMed Scopus (219) Google Scholar, 9Jamal M.M. Sony A. Quinn P.G. Wheeler D.E. Arora S. Johnston D.E. Clinical features of hepatitis C-infected patients with persistently normal alanine transaminase levels in the Southwestern United States.Hepatology. 1999; 30: 1307-1311Crossref PubMed Scopus (128) Google Scholar, 30Pradat P. Alberti A. Poynard T. Esteban J.I. Weiland O. Marcellin P. et al.Predictive value of ALT levels for histologic findings in chronic hepatitis C: a European Collaborative Study.Hepatology. 2002; 36: 973-977PubMed Google Scholar]. In fact, although some of these subjects have marked liver damage at biopsy, the findings that the majority of HCV carriers with PNAL show weaker histologic activity and fibrosis, that the progression rate of fibrosis is significantly slower than in patients with elevated ALT, and that these subjects at present can not be offered antiviral treatment outside of clinical trials, make it difficult to recommend routine liver biopsy for all HCV carriers with PNAL [3Bacon B.R. Treatment of patients with Hepatitis C and normal serum aminotransferase levels.Hepatology. 2002; 36: S179-S184Crossref PubMed Google Scholar, 16Puoti C, Guido M, Mangia A, Persico M, Prati D. Italian Study for the Study of the Liver (AISF) ad hoc Committee ‘HCV carriers with persistently normal ALT levels’. On-line final statement. http://www.webaisf.org.Google Scholar]. Furthermore, biopsy is an invasive procedure with risk of serious complications, economic costs and poor patient compliance. In the near future, if combination therapy with PEG-IFN plus ribavirin will be approved also for HCV carriers with PNAL, liver biopsy will be necessary in order to select patients candidates to therapy and to identify those with normal liver or minimal disease. Since then, in clinical practice liver biopsy should be reserved to particular clinical situations, e.g. for patients with long life expectancy or in the cases for whom the knowledge of histological data may be crucial for the clinical management [[16]Puoti C, Guido M, Mangia A, Persico M, Prati D. Italian Study for the Study of the Liver (AISF) ad hoc Committee ‘HCV carriers with persistently normal ALT levels’. On-line final statement. http://www.webaisf.org.Google Scholar]. In conclusion, the majority of HCV carriers with normal ALT have mild degree of inflammation and fibrosis and non progressive disease. Nevertheless, some of them might progress towards more severe liver disease. These patients should be followed up at regular intervals in order to identify ALT flares or disease progression. Preliminary data show that antiviral combination treatment gives SVR similar to that obtained in patients with abnormal aminotransferase levels. However, given the scarcity of data, the potential risks of such treatment and the histological mildness and slow progression of the disease in these patients, until the results of studies with PEG-IFN plus ribavirin are available and the cost-effectiveness of these new options have been investigated, HCV carriers with normal ALT should not receive antiviral treatment outside clinical trials. Many questions remain still unanswered: is the natural history of the HCV infection different in subjects with PNAL and in patients with minimally raised ALT? Is CHC the same entity in subjects with persistently normal ALT and in patients with sporadic ALT flare-ups? Finally: what should we treat, the test (ALT) or the disease (liver damage)? [[36]Puoti C. Magrini A. Stati T. Rossi P. Montagnese F. Resta S. Interferon for hepatitis C [research Letter].Lancet. 1997; 349: 398-399Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar]. The solution of these conundrums will come from well-sized, long-term prospective studies.
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