Towards more individualised management of hepatitis C virus patients with initially or persistently normal alanineaminotransferase levels
2004; Elsevier BV; Volume: 42; Issue: 2 Linguagem: Inglês
10.1016/j.jhep.2004.12.004
ISSN1600-0641
Autores Tópico(s)Hepatitis B Virus Studies
ResumoInfection with the hepatitis C virus (HCV) is currently a major cause of chronic hepatitis, cirrhosis, end-stage liver disease and hepatocellular carcinoma in most Western Countries where it represents the most frequent reason for liver transplantation [[1]Hoofnagle J.H. Hepatitis C: the clinical spectrum of disease.Hepatology. 1997; 26: 15S-20SCrossref PubMed Scopus (697) Google Scholar]. The clinical features associated with chronic HCV infection are highly heterogeneous and the natural course of the underlying liver disease is also extremely variable and still not fully understood [2Marcellin P. Hepatitis C: the clinical spectrum of the disease.J Hepatol. 1999; 31: 9-16Abstract Full Text PDF PubMed Google Scholar, 3Alberti A. Chemello L. Benvegnù L. Natural history of hepatitis C.J Hepatol. 1999; 31: 17-24Abstract Full Text PDF PubMed Google Scholar]. 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 [1Hoofnagle J.H. Hepatitis C: the clinical spectrum of disease.Hepatology. 1997; 26: 15S-20SCrossref PubMed Scopus (697) Google Scholar, 2Marcellin P. Hepatitis C: the clinical spectrum of the disease.J Hepatol. 1999; 31: 9-16Abstract Full Text PDF PubMed Google Scholar, 3Alberti A. Chemello L. Benvegnù L. Natural history of hepatitis C.J Hepatol. 1999; 31: 17-24Abstract Full Text PDF PubMed Google Scholar, 4Yeo A.E.T. Ghany M. Conry-Cantilena C. Melpolder J.C. Kleiner D.E. Shih J.W.K. et al.Stability of HCV-RNA level and its lack of correlation with disease severity in asymptomatic chronic hepatitis C virus carriers.J Viral Hepatitis. 2001; 8: 256-263Crossref PubMed Scopus (41) Google Scholar]. 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 [5Shakil 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 (269) Google Scholar, 6Serfaty L. Nousbaum J.B. Elghouzzi M.H. Giral P. Legendre C. Poupon R. Prevalence, severity, and risk factors of liver disease in blood donors positive in a second-generation anti-hepatitis C virus screening test.Hepatology. 1995; 21: 725-729PubMed Google Scholar, 7Conry-Cantilena C. VanRaden M. Gibble J. Melpolder J. Shakil A.O. Viladomiu L. et al.Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection.N Engl J Med. 1996; 334: 1691-1696Crossref PubMed Scopus (597) Google Scholar, 8Piton A. Poynard T. Imbert-Bismut F. Khalil L. Delattre J. Pelissier E. for the MULTIVIRC Group 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 (266) Google Scholar]. 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’ [9Puoti C. HCV carriers with persistently normal aminotransferase levels: normal does not always mean healthy.J Hepatol. 2003; 38: 529-532Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 10Prieto 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]. Many patients maintain persistently normal ALT levels over a long-term follow-up but a significant subgroup shows biochemical reactivation over time [11Puoti C. Castellacci R. Montagnese F. Zaltron S. Stornaiuolo G. Bergami N. et al.Histological and virological features and follow-up of HCV carriers with normal aminotransferase levels: the Italian Study of the Asymptomatic C Carriers (ISACC).J Hepatol. 2002; 37: 117-123Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 12Martinot-Peignoux M. Boyer N. Cazals-Hatem D. Pham B.-N. Gervais A. Le Breton V. 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 (142) Google Scholar, 13Alberti A. Benvegnù L. Boccato S. Ferrari A. Sebastiani G. Natural history of initially mild chronic hepatitis C.Dig Liver Dis. 2004; 36: 646-654Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar]. 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 [9Puoti C. HCV carriers with persistently normal aminotransferase levels: normal does not always mean healthy.J Hepatol. 2003; 38: 529-532Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 13Alberti A. Benvegnù L. Boccato S. Ferrari A. Sebastiani G. Natural history of initially mild chronic hepatitis C.Dig Liver Dis. 2004; 36: 646-654Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar]. Accordingly, recent guidelines and management recommendations indicate that viremic patients with normal ALT should not be considered to be ‘healthy carriers’ [14National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C: 2002—June 10–12. Hepatology 2002;36:S3–20Google Scholar, 15Strader D.B. Wright T. Thomas D.L. Seeff L.B. Diagnosis management and treatment of hepatitis C.Hepatology. 2004; 39: 1147-1171Crossref PubMed Scopus (1573) Google Scholar, 16Booth J.C. O'Grady J. Neuberger J. Clinical guidelines on the management of hepatitis C.Gut. 2001; 49: I1-I21Crossref PubMed Google Scholar]. 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 [17Foster G.R. Goldin R.D. Thomas H.C. Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis.Hepatology. 1998; 27: 209-212Crossref PubMed Scopus (509) Google Scholar, 18von Wagner M. Lee J.-H. Friedl R. Kronenberger B. Sarrazin C. Zeuzem S. Impaired quality of life in patients with chronic hepatitis C and persistently normal aminotransferase levels.Hepatology. 2003; 34 (abstract 606): 454ACrossref Google Scholar]. 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]Zeuzem S. Diago M. Gane E. Reddy R. Pockros P. Prati D. for the PEGASYS Study NR16071 Investigator Group et al.Peginterferon alfa-2a (40 KD) and ribavirin in patients with chronic hepatitis C and normal aminotransferase levels.Gastroenterology. 2004; 127: 1724-1732Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar]. 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. There have been discussions and debates on how to define and diagnose the subgroup of HCV patients with normal ALT and different definitions have been proposed for this category. The debate has been focused on two different issues: (1) which is the most appropriate cut-off for defining ALT normality in individuals chronically infected with HCV; (2) which is the most appropriate time frame and algorithm for defining that ALT are indeed ‘persistently’ normal. It is well known that ALT levels vary according to a wide variety of different factors including gender, body mass index, alcohol consumption, smoking and medications [8Piton A. Poynard T. Imbert-Bismut F. Khalil L. Delattre J. Pelissier E. for the MULTIVIRC Group 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 (266) 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 levels.Ann Intern Med. 2002; 137: 1-10Crossref PubMed Scopus (1095) Google Scholar]. The results of a recent study question the concept of a universal definition of ‘normal’ ALT range [[20]Prati D. Taioli E. Zanella A. della Torre E. Butelli S. del Vecchio E. et al.Updated definitions of healthy ranges for serum alanine aminotransferase levels.Ann Intern Med. 2002; 137: 1-10Crossref PubMed Scopus (1095) Google Scholar]. The authors hypothesize that inclusion of patients with undiagnosed HCV infection has led to an overestimate of the ‘normal’ ranges that are in wide use. In a survey of Italian blood donors, serum ALT activity was independently related to body mass index and laboratory markers of abnormal lipid and carbohydrate metabolism. The use of downwardly revised definitions of normal ALT levels in men and women were useful in identifying HCV-infected individuals with histological lesions. These results suggest that the use of a term such as ‘normal’ when referring to patients with HCV infection may no longer be appropriate or needs to be revised. It is most likely that with the current cut-off limits we are underestimating the number of cases with HCV infection who have slightly abnormal ALT and an underlying histologically active chronic hepatitis C. This is in agreement with findings that the type of liver lesions seen in the biopsy are quite similar in HCV patients with normal or slightly abnormal ALT levels [21Puoti 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 or abnormal alanine transaminase levels.Hepatology. 1997; 26: 1393-1398Crossref PubMed Scopus (219) Google Scholar, 22Montalto G. Zignego A.L. Ruggeri M.I. Giannini C. Soresi M. Monti M. et al.Serum HCV-RNA and liver histologic findings in patients with long-term normal transaminases.Dig Dis Sci. 1997; 42: 1703-1707Crossref PubMed Scopus (28) Google Scholar]. Persistently normal ALT (PNALT) levels in patients with chronic hepatitis C has historically been defined as the presence of three consecutive measurements within the normal range during a 6-month period [23EASL International Consensus Conference on Hepatitis C. Paris, 26–28, February 1999, Consensus Statement. European Association for the Study of the Liver. J Hepatol 1999;30:956–61.Google Scholar, 24Marcellin P. Levy S. Erlinger S. Therapy of hepatitis C: patients with normal aminotransferase levels.Hepatology. 1997; 26: 133S-136SCrossref PubMed Scopus (165) Google Scholar]. However, the length of the observational period and the number of ALT determinations needed to precisely identify a patient with PNALT has been widely discussed. According to a recent study conducted in Italy [[11]Puoti C. Castellacci R. Montagnese F. Zaltron S. Stornaiuolo G. Bergami N. et al.Histological and virological features and follow-up of HCV carriers with normal aminotransferase levels: the Italian Study of the Asymptomatic C Carriers (ISACC).J Hepatol. 2002; 37: 117-123Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar], at least an 18-month period of prospective observation has been proposed to ensure that ALT levels are indeed persistently within the ‘normal’ range in an HCV-infected individual. However, even in such cases, late ALT reactivation may occur, as was observed in HCV patients with PNALT who had been followed for many years. This study was important in underlying that the shorter the baseline observation is, the higher the risk of classifying a patient as having normal ALT who will not have them ‘persistently’ normal. However, from a practical point of view, a 6-month baseline with at least 2–3 separate ALT determinations might still be taken as the current standard for defining this group of patients, while considering that ALT reactivation will occur in around 15–20% of these cases at further follow-up, thus establishing the need for ALT monitoring in all patients initially defined as HCV patients with PNALT. The definition of HCV patients with persistently normal ALT (PNALT) should be preferred to that of ‘healthy HCV carriers’ or ‘asymptomatic HCV carriers’ since, as discussed later in this review, these patients have a chronic infection that is ‘per se’ an unhealthy condition and often have some kind of liver disease and a quality of life that can be impaired as in HCV patients with abnormal ALT. To better define the baseline observation one can add indication of the length of observed ALT normality (3 mo-PNALT, 6 mo-PNALT, 12 mo-PNALT, etc.). Significant variations in the prevalence of HCV patients with PNALT have been reported, as a consequence of selection and definition criteria [5Shakil 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 (269) Google Scholar, 6Serfaty L. Nousbaum J.B. Elghouzzi M.H. Giral P. Legendre C. Poupon R. Prevalence, severity, and risk factors of liver disease in blood donors positive in a second-generation anti-hepatitis C virus screening test.Hepatology. 1995; 21: 725-729PubMed Google Scholar, 7Conry-Cantilena C. VanRaden M. Gibble J. Melpolder J. Shakil A.O. Viladomiu L. et al.Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection.N Engl J Med. 1996; 334: 1691-1696Crossref PubMed Scopus (597) Google Scholar, 8Piton A. Poynard T. Imbert-Bismut F. Khalil L. Delattre J. Pelissier E. for the MULTIVIRC Group 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 (266) Google Scholar]. Large population studies indicate that the prevalence among chronically infected individuals is most likely around 30–50%. In our own study of the general population in Northern Italy (Telecom Study) the prevalence of HCV patients with PNALT was 46% among infected persons, being rather constant in different age subgroups, and was 0.79% in the adult general population screened [[25]Alberti A. Noventa F. Benvegnù L. Boccato S. Gatta A. Prevalence of liver disease in a population of asymptomatic individuals with hepatitis C virus infection.Ann Intern Med. 2002; 137: 961-964Crossref PubMed Scopus (144) Google Scholar]. Many studies have described prevalence, entity and type of histological lesions that can be found in the liver biopsy of HCV carriers with persistently normal ALT, after our early demonstration that ‘significant’ liver lesions can be present in these subjects [[26]Alberti A. Morsica G. Chemello L. Cavalletto D. Noventa F. Pontisso P. et al.Hepatitis C viraemia and liver disease in symptom-free individuals with anti-HCV.Lancet. 1992; 340: 697-698Abstract PubMed Scopus (403) Google Scholar]. Most published studies agree on the conclusion that around two thirds of HCV patients with PNALT have no or minimal activity and/or fibrosis in their liver biopsy [27Hui C.K. Monto A. Belaye T. Lau E. Wright T.L. Outcomes of interferon alpha and ribavirin treatment for chronic hepatitis C in patients with normal serum aminotransaminase.Gut. 2003; 52: 1644-1648Crossref PubMed Scopus (40) Google Scholar, 28Shiffman M.L. Stewart C.A. Hofmann C.M. Contos M.J. Luketic V.A. Sterling R.K. et al.Chronic infection with hepatitis C virus in patients with elevated or persistently normal serum alanine aminotransferase levels: comparison of hepatic histologic and response to interferon therapy.J Infect Dis. 2000; 182: 1595-1601Crossref PubMed Scopus (75) Google Scholar, 29Erardt A. Behlen-Wilm U. Adams O. Donner A. Heintges T. Haussinger D. Combination treatment of IFN alpha2b and ribavirin in patients with chronic hepatitis C and persistently normal ALTs.Dig Dis Sci. 2003; 48: 921-925Crossref PubMed Scopus (12) Google Scholar, 30Nutt A.K. Hassan H.A. Lindsey J. Lamps L.W. Raufman J.P. Liver biopsy in the evaluation of patients with chronic hepatitis C who have repeatedly normal or near-normal serum alanine aminotransferase levels.Am J Med. 2000; 109: 62-64Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 31Herve S. Savoye G. Riachi G. Hellot M.F. Goria O. Lerebours E. et al.Chronic hepatitis C with normal or abnormal aminotransferase levels: is it the same entity?.Eur J Gastroenterol Hepatol. 2001; 13: 405-500Crossref PubMed Scopus (23) Google Scholar, 32Pradat 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: 973-977Crossref PubMed Google Scholar, 33Renou C. Halfon P. Pol S. Cacoub P. Jouve E. Bronowicki J.P. et al.Histological features and HLA class II alleles in hepatitis C virus chronically infected patients with persistently normal alanine aminotransferase levels.Gut. 2002; 51: 585-590Crossref PubMed Scopus (69) Google Scholar, 34Jamal M.M. Soni A. Quinn P.G. Wheeler D.E. Arora S. Johnston D.E. Clincial features of hepatitis C-infected patients with persistently normal alanine transaminase levels in the Southwestern United States.Hepatology. 1999; 30: 1307-1311Crossref PubMed Scopus (125) Google Scholar]. On the other hand, significant fibrosis (≥F2 by the METAVIR classification) has been reported in 5–30% of the cases, with large variations among studies due to the quite different inclusion criteria and length of baseline follow-up. A subgroup of these cases has advanced fibrotic changes (F3 or F4, i.e. cirrhosis). The cumulative percentage of HCV patients with PNALT who have significant (≥F2 by METAVIR) fibrosis in liver biopsy among 1154 such cases included in 23 published studies was 22% [[13]Alberti A. Benvegnù L. Boccato S. Ferrari A. Sebastiani G. Natural history of initially mild chronic hepatitis C.Dig Liver Dis. 2004; 36: 646-654Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar], a figure that is consistent with what we have observed in our general population-based survey where significant fibrosis was detected in 18.7% of HCV patients with PNALT [[25]Alberti A. Noventa F. Benvegnù L. Boccato S. Gatta A. Prevalence of liver disease in a population of asymptomatic individuals with hepatitis C virus infection.Ann Intern Med. 2002; 137: 961-964Crossref PubMed Scopus (144) Google Scholar]. The prevalence of cases with significant fibrosis was usually higher in those studies in which HCV patients with PNALT had undergone liver biopsy after a shorter baseline observation period or with fewer ALT tests, as shown in Fig. 1 that describes the relative prevalence of the different stage of fibrosis stage of fibrosis derived from studies in which the baseline ALT evaluation period was clearly indicated. The prevalence of cirrhosis in HCV patients with PNALT has ranged from 1 to 6% in various studies and one study reported that up to 29% of these individuals have stage 3 or 4 fibrosis. Although the extent of histological damage can be significant, there is debate as to whether patients with normal ALT levels have a lesser degree of liver damage than those with elevated ALT levels. A recently published longitudinal study in a cohort of 123 patients [[35]Ghany M.G. Kleiner D.E. Alter H. Doo E. Khokar F. Promrat K. et al.Progression of fibrosis in chronic hepatitis C.Gastroenterology. 2003; 124: 97-104Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar] revealed a significant association between ALT levels and progression of fibrosis. In a further longitudinal study, significantly lower global Knodell scores and HAI scores were observed in patients with normal ALT levels than in those with elevated ALT levels [[36]Herve S. Savoye G. Riachi G. Hellot M.F. Goria O. Lerebours E. et al.Chronic hepatitis C with normal or abnormal aminotransferase levels: is it the same entity?.Eur J Gastroenterol Hepatol. 2001; 13: 495-500Crossref PubMed Scopus (39) Google Scholar]. Moreover, consistently lower scores for portal inflammation, piecemeal necrosis, lobular inflammation and fibrosis were found in case-control studies, although most patients will have some form of liver lesion, even in the presence of normal ALT levels [36Herve S. Savoye G. Riachi G. Hellot M.F. Goria O. Lerebours E. et al.Chronic hepatitis C with normal or abnormal aminotransferase levels: is it the same entity?.Eur J Gastroenterol Hepatol. 2001; 13: 495-500Crossref PubMed Scopus (39) Google Scholar, 37Pradat 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: 973-977Crossref PubMed Scopus (188) Google Scholar]. In other studies, however, the degree of liver injury seen in HCV patients with PNALT did not differ significantly from matched controls with elevated ALT [[21]Puoti 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 or abnormal alanine transaminase levels.Hepatology. 1997; 26: 1393-1398Crossref PubMed Scopus (219) Google Scholar]. If it is clear from these studies that a subgroup of HCV patients with PNALT have significant liver disease at liver biopsy, what about the course of liver disease and long-term outcomes in these patients? Unfortunately, there have been few studies assessing longitudinally the natural course of liver disease in HCV patients with PNALT and most of them have included rather small series of patients. The rate of progression of liver fibrosis in HCV patients with PNALT appears to be generally slower than in those with elevated ALT levels [38Mathurin P. Moussalli 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 (296) Google Scholar, 39Persico M. Persico E. Suozzo R. Conte S. de Seta M. Coppola L. et al.Natural history of hepatitis C virus carriers with persistently normal aminotransferase levels.Gastroenterology. 2000; 118: 760-764Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 40Hui 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 (120) Google Scholar, 41Boccato S, Pistis R, Noventa F, Benvegnù L, Alberti A. Fibrosis progression in initially mild chronic hepatitis C. Submitted.Google Scholar]. On average, the rate of fibrosis progression was calculated to be around half of that seen for patients with elevated ALT, and to be on average around 0.05–0.06 point of fibrosis per year in the METAVIR scale when assessed by the ratio between stage of fibrosis and estimated duration of the infection. Although slower, progression of fibrosis does occur in a subgroup of HCV patients with PNALT even when ALT remains persistently normal in long-term sequential testing, and this conclusion is evidence-based. In studies with a rather short follow-up (<5 years), most of the HCV patients with PNALT did not show any significant progression of disease as long as ALT remained normal (Table 1). On the other hand, Hui et al. [[40]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 (120) Google Scholar] reported significant progression of liver fibrosis while ALT levels were persistently normal in 22% of HCV patients followed up for a mean period of 6.3 years, and 5% developed histologic evidence of cirrhosis. Interestingly, all patients who showed progression to F3 or F4 had F2 in the initial biopsy. Very similar findings were recently obtained in our Unit [[41]Boccato S, Pistis R, Noventa F, Benvegnù L, Alberti A. Fibrosis progression in initially mild chronic hepatitis C. Submitted.Google Scholar]. In a longitudinal study aimed to assess the histological outcomes in patients with mild chronic hepatitis C and in HCV patients with PNALT, a second liver biopsy was taken after a mean interval of 7.3 years and showed progression of fibrosis from F0 to F1 in 15% of the cases, from F1 to F2 in 8% and from F2 to F3 in 20% and from F2 to F4 (cirrhosis) in 9%, despite ALT levels being confirmed ‘normal’ at annual testing. Progression of liver fibrosis in HCV patients with PNALT has also been reported by Ryder et al. [[42]Ryder S.D. on behalf of the Trent Hepatitis C Study Group Progression of hepatic fibrosis in patients with hepatitis C: a prospective repeat liver biopsy study.Gut. 2004; 53: 451-455Crossref PubMed Scopus (238) Google Scholar] and by Cividini et al. [[43]Cividini A. Rebucci C. Silini E. Mondelli M.U. Is the natural history of hepatitis C virus carriers with normal aminotransferase really benign?.Gastroenterology. 2001; 121: 1526-1527Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar].Table 1Histologic outcome in HCV patients with PNALT undergoing follow-up liver biopsyAuthorN° casesMean time interval between biopsies% Fibrosis progressionSangiovanni et al., 1998 [56]Sangiovanni A. Morales R. Spinzi G.C. Rumi M. Casiraghi A. Ceriani R. et al.Interferon alfa treatment of HCV RNA carriers with persistently normal transaminase levels: a pilot randomized controlled study.Hepatology. 1998; 27: 853-856Crossref PubMed Scopus (102) Google Scholar61.5 yearsNoneMartinot-Peignoux et., 2001 [12]Martinot-Peignoux M. Boyer N. Cazals-Hatem D. Pham B.-N. Gervais A. Le Breton V. 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 (142) Google Scholar243.5 yearsNoneGhany et al., 2003 [35]Ghany M.G. Kleiner D.E. Alter H. Doo E. Khokar F. Promrat K. et al.Progression of fibrosis in chronic hepatitis C.Gastroenterology. 2003; 124: 97-104Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar163.8 yearsNonePersico et al., 2000 [39]Persico M. Persico E. Suozzo R. Conte S. de Seta M. Coppola L. et al.Natural history of hepatitis C virus carriers with persistently normal aminotransferase levels.Gastroenterology. 2000; 118: 760-764Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar255 yearsNoneHui et al., 2003 [40]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 (120) Google Scholar406.3 years22.5%Ryder et al., 2004 [42]Ryder S.D. on behalf of the Trent Hepatitis C Study Group Progression of hepatic fibrosis in patients with hepatitis C: a prospective repeat liver biopsy study.Gut. 2004; 53: 451-455Crossref PubMed Scopus (238) Google Scholar462.5 years22%Boccato et al., 2004 [41]Boccato S, Pistis R, Noventa F, Benvegnù L, Alberti A. Fibrosis progression in initially mild chronic hepatitis C. Submitted.Google Scholar327.8 years28%Cividini et al., 2001 [43]Cividini A. Rebucci C. Silini E. Mondelli M.U. Is the natural history of hepatitis C virus carriers with normal aminotransferase really benign?.Gastroenterology. 2001; 121: 1526-1527Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar186 years17% Open table in a new tab HCV patients with initially and persistently normal ALT levels may also show disease progression at long-term follow-up as a consequence of transient ALT flares or of persistent biochemical reactivation of their liver disease. All published studies confirm that HCV patients with PNALT ar
Referência(s)