1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References

The course of hepatitis C virus (HCV) infection carriers with normal/near-normal aminotransferases (NALT) is usually mild; however, in a few, fibrosis progression occurs. We aimed to verify whether monitoring by liver biopsy might be replaced by noninvasive methods and to identify factors associated with fibrosis progression in patients with persistently normal alanine aminotransferases. We studied 40 untreated HCV-RNA–positive subjects (22 male; median age, 44 years), who underwent two liver biopsies, with a median interval of 78.5 months, during which alanine aminotransferase concentrations (median number of determinations: 12) never exceeded 1.2 times the upper normal limit. Within 9 months from the second biopsy, they were tested by the shear elasticity probe (Fibroscan) and the artificial intelligence algorithm FibroTest. METAVIR fibrosis scores were analyzed in relationship to demographic, clinical, and viral parameters. Weighted kappa analysis was used to verify whether the results of noninvasive methods agreed with histology. Significant fibrosis (≥F2), present at the first biopsy in only one patient (2.5%), was observed at the second biopsy in 14 patients (35%). At multivariate analysis, excess alcohol consumption in the past (>20 g/d; P = .017) and viral load (>8.0 × 106 copies/mL; P = .021) were independent predictors of progression. In identifying patients with significant fibrosis, inter-rater agreement was excellent for Fibroscan (weighted kappa = 1.0), and poor for FibroTest (weighted kappa = −0.041). In conclusion, among HCV carriers with NALT, Fibroscan is superior to the FibroTest in the noninvasive identification of fibrosis, for which excess alcohol consumption in the past and high viral load represent risk factors. (HEPATOLOGY 2005.)

Serum alanine aminotransferase (ALT) concentration, the most widely used indirect marker for liver disease activity, remains within the normal range in approximately 25% to 30% of chronic hepatitis C virus (HCV) carriers, and another 40% have ALT levels less than 2 times the upper limit of normal.1, 2 Although the exact definition of what is meant by persistent “normality” of ALT is discussed,3 it is generally accepted that the natural history of the subgroup of HCV carriers who have persistently normal or minimally elevated ALT levels (NALT) is characterized by a slower progression rate.4 Nevertheless, these patients can have progressive liver disease and develop advanced fibrosis or cirrhosis.5 Thus, to decide whether and when to start antiviral treatment might require watchful waiting with periodic liver biopsy, a strategy unlikely to meet patients' favor. Besides, according to a recent study, such a strategy would lead to higher costs, increased cumulative incidence of cirrhosis, and decreased survival in comparison with “empiric” treatment, though allowing avoidance of treatment in many patients.6 Reliable and inexpensive noninvasive methods to assess fibrosis progression could not be better appreciated than in this setting.

So far, the two methods that have been found most promising to supersede liver biopsy in the assessment of liver fibrosis are a patented artificial intelligence algorithm (FibroTest; BioPredictive, Paris, France)7, 8 and a technique to measure in vivo liver elasticity, based on 1-dimensional transient elastography (Fibroscan, EchoSens, Paris, France).9, 10 To the best of our knowledge, FibroTest and Fibroscan have not yet been validated in HCV carriers with NALT, although their use in combination in patients with chronic hepatitis C has been recently advocated.11 We compared the ability of FibroTest and Fibroscan to identify HCV carriers with NALT and histologically documented progression to significant fibrosis; in addition, we took the opportunity to further explore factors associated with fibrosis progression in this category of HCV patients.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References


From November 1, 1995, to May 31, 1998, 58 consecutive, unselected, anti-HCV and HCV-RNA–positive subjects with normal aminotransferases were evaluated at a liver disease outpatient clinic by one of us (C.C.). In all cases, after a thorough physical examination and liver ultrasonography, ALT concentrations were monitored monthly for 6 months. At the end of this observation period, all patients underwent a percutaneous liver biopsy. Those patients who, on the repeat testing, had, on at least one occasion, ALT >1.2 times the upper limit of the reference range (n = 13), or had Ishak staging score12 higher than 2 at liver biopsy (n = 3), were excluded. The 42 remaining patients received strong advice on lifestyle issues (including ideal body weight and alcohol consumption), but no antiviral treatment. Along a median follow-up period of 78.5 months (range, 62–87) during which ALT were measured at least twice yearly, a further 2 patients were excluded because, on at least one occasion, ALT increased to >1.2 times the upper limit of the reference range. The study population consists of the remaining 40 patients, who were offered a second liver biopsy, as well as evaluation of liver fibrosis by means of noninvasive methods. All patients gave written informed consent to their participation to the study, which was conducted in strict adherence to the principles of the Declaration of Helsinki.

The main characteristics of patients at the time of second biopsy are presented in Table 1. HCV positivity had been discovered on the occasion of a blood donation (n = 2), during family screening of anti-HCV–positive patients (n = 28), after routine medical checkups (n = 6) or after systematic blood testing in risk groups (n = 4). None was coinfected with hepatitis B virus or HIV, had autoimmune hepatitis or genetic liver disease, or was under immunosuppressive treatment or renal replacement therapy. Four patients had a history of intravenous drug use, and two were exposed to blood products before 1990; the median duration of infection in these six patients was estimated to be 11 years (range, 5–20 years). No reliable estimate of the duration of infection was possible in the remaining 34 patients.

Table 1. Main Demographic and Clinical Features of the Studied Population (N = 40)
  • NOTE. Data are presented as medians (range) for continuous variables, and as frequencies (%) for categorical variables.

  • *

    >20 g/d.

  • Upper normal limits were 40 and 36 U/L for males and females, respectively.

Male sex22 (55)
Age, years43.5 (27–66)
Body mass index, kg/m221 (18–26)
HCV genotype 
 HCV-112 (30)
 HCV-217 (42.5)
 HCV-38 (20)
 HCV-43 (7.5)
Excess alcohol consumption in the past*10 (25)
Carbohydrate-deficient transferrin 
 >2.03%0 (0)
 1.7%–2.03%1 (2.5)
 <1.7%39 (97.5)
ALT, U/L37.5 (23–42)
Total bilirubin, mg/dL0.95 (0.5–1.1)
International Normalized Ratio, Units1 (0.95–1.16)
Platelets, ×109/L248 (180–297)
Plasma cholesterol, mg/dL148 (118–199)

Along the years elapsed since first identified as HCV carriers, the study patients underwent a total of 844 ALT measurements (median, 20; range, 17–26): in 795 (94%) of 844 cases, they were within the normal range. Moreover, during the time elapsed between the first and the second biopsy, they underwent 502 total ALT measurements (median, 12; range, 11–15), which were within the normal range in 483 (96%) of 502 cases. Fifteen patients (37.5%) had ALT that never exceeded the upper limit of the reference range.

Analytical Methods.

ALT measurements were performed on an automated Shimadzu CL-7300 system (Shimadzu Corp., Tokyo, Japan) using Roche Diagnostics reagents (Rotkreuz, Switzerland). The upper normal limits were 40 and 36 U/L for males and females, respectively. Gamma-glutamyltranspeptidase (GGT) and total bilirubin were assessed by the automated Hitachi 917 analyzer using Roche Diagnostics reagents. Apolipoprotein A1, α2-macroglobulin, and haptoglobin were determined in serum samples by using an automatic nephelometer BNII (Dade Behring, Marburg, Germany). Carbohydrate-deficient transferrin was measured by means of high-performance liquid chromatography (Bio-Rad Laboratories, Segrate, Italy): the cutoff limits adopted by the manufacturer were greater than 2.3% of total transferrin for problem drinkers, and less than 1.7% for abstemious persons; values between 1.7% and 2.3% were considered undetermined.

Viral Studies.

Anti-HCV was detected by means of a third-generation ELISA (AxSYM HCV version 3.0; Abbott Laboratories, Abbott Park, IL). Serum samples were collected for detection, quantitation, and typing of HCV-RNA. Qualitative serum HCV-RNA detection was performed with reverse transcriptase polymerase chain reaction in the 5′-noncoding region of the HCV genome (Roche COBAS Amplicor HCV Test, version 2.0: Roche Diagnostics). Quantification was performed by means of branched DNA with the Bayer's VERSANT bDNA 3.0 assay (Bayer Diagnostics, Emeryville, CA). The detection threshold was 3,200 copies (615 International Units) per mL. HCV genotyping was performed with INNO-LIPA HCV II (Innogenetics, Gent, Belgium).

Liver Histology.

Liver biopsy sections were formalin-fixed, paraffin-embedded, and stained routinely with hematoxylin-eosin. The specimens, obtained by means of Menghini needles, diameter 1.6 mm, had an average length of 20 ± 3 mm (range, 14–25 mm) and included a median number of 7 portal triads (range, 4–12). Histological results, originally reported according to the Ishak scoring system,12 were, for the purposes of this study, reclassified according to the METAVIR scoring system13 by a single, experienced pathologist blinded to both clinical data and results of noninvasive tests. The METAVIR and Ishak systems assign numeric (integer) values to stage fibrosis based on architectural changes and to grade inflammation based on the degree of necroinflammatory lesions, with good reproducibility but also some inter- and intra-observer variability: this is why one of the initial biopsies, originally reported as having an Ishak staging score 2, was reclassified as METAVIR F2. Steatosis was graded according to the method proposed by Brunt et al.14

Noninvasive Detection of Fibrosis.

Fresh serum samples were analyzed for the set of variables included in the FibroTest score, a patented artificial intelligence algorithm previously shown to generate an accurate estimate of the liver fibrosis stage in patients with hepatitis C. All patients were also evaluated by means of the shear elasticity probe, a device based on 1-dimensional transient elastography, well adapted to the study of liver elasticity (Fibroscan). For a more detailed description of this technique and of the examination procedure, the reader is referred to the paper by Sandrin et al.10 Each patient underwent a fixed series of 20 successful acquisitions.

Both FibroTest and Fibroscan were performed by external personnel, not involved in the planning of the study or in the analysis of data, strictly blinded to histological results, and only aware that the study population consisted of HCV carriers with NALT. Furthermore, patients were requested not to release any information concerning their illness during Fibroscan measurements.

Statistical Analysis.

Statistical analysis of the data was performed by means of the statistical software packages BMDP/Dynamic, release 7.0 (Statistical Software Ltd., Cork, Ireland) and MedCalc, version (MedCalc Software, Mariakerke, Belgium). Shapiro and Wilk's W test was applied to test normality of continuous data. Because data demonstrated a significant departure from normal distribution, they were analyzed by nonparametric methods (Mann-Whitney test, Wilcoxon test), and medians were chosen as measures of central tendency, with ranges indicating variability. The associations between categorical variables were explored by means of the Fisher's exact test. The risk of developing significant fibrosis (METAVIR fibrosis stage F2 or greater) was analyzed in relationship to possible confounding factors, to express the relative risk they conferred with regard to such outcome. Logistic regression analysis with a stepwise forward approach was used to identify, among the set of variables associated (P < .10) with progression to significant fibrosis at the second liver biopsy, the independent predictors of outcome. The degree of inter-rater agreement between different categorization schemes (METAVIR, Ishak) and different methods to evaluate liver fibrosis (histology, noninvasive methods) was measured by performing weighted kappa analysis. P values were considered significant when equal to or below .05, and were two-tailed.


  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References


None of the patients had symptoms of liver disease. All declared to have adopted, since the time of the initial evaluation for HCV seropositivity, measures for a healthy lifestyle. In particular, none of them became obese; in fact, at the second liver biopsy, five had a body mass index (BMI) equal to or greater than the threshold defining overweight (25 kg/m2), in comparison to 4 at the time of the first liver biopsy, but none reached a BMI ≥27 kg/m2. At the first liver biopsy, median BMI was 21 kg/m2 (range, 19–25; interquartile range, 3.75 kg/m2); at the second liver biopsy, median BMI was 21 kg/m2 (range, 18–26; interquartile range, 3 kg/m2). In the interval between the 2 biopsies, BMI decreased in 11 (27.5%) of 40, remained unchanged in 8 (20.0%) of 40, and increased in 21 (52.5%) of 40, with variations between initial and final BMI ranging from −4 kg/m2 to +3 kg/m2. All patients reported to adhere to strict avoidance of alcohol consumption, including 10 who admitted to having consumed excess alcohol (defined by a threshold >20 g/d, in accordance with Italian drinking guidelines15) in the past, when still unaware of HCV positivity. Specifically, drinking habits in the past were reported in the order of 30 g/d by 7 patients, 40 g/d by 2, and 50 g/d by 1. In the interval between the two biopsies, none of the patients was found to have GGT concentrations above 1.5 times the upper limit of the normal range, or to display clinical signs of ethanol abuse. Finally, at the time of the second biopsy, none of the patients had serum carbohydrate-deficient transferrin concentrations above the threshold indicating heavy drinking.


Agreement between the METAVIR and the Ishak scoring systems was fair with regard to categorization of necroinflammatory activity (weighted kappa = 0.66) and good for fibrosis (weighted kappa = 0.803). Table 2 presents the distribution of histological activity scores at the two liver biopsies. The median activity scores were A1 at the first, and A2 at the second biopsy, respectively, whereas the median fibrosis score was F1 at both biopsies. However, at the second biopsy, fibrosis was found to be progressed to a significant degree (METAVIR fibrosis score F2 or greater) in approximately one third of patients. In detail, of the 7 patients with fibrosis score F0 at the first biopsy, 2 remained F0 and 5 progressed to F1. Of the 32 patients with fibrosis score F1 at the first biopsy, 1 regressed to F0, 18 remained F1, 9 progressed to F2, and 4 to F3. The single patient with F2 at the first biopsy progressed to F3. Moreover, significantly more necroinflammatory activity (P < .001) and fibrosis (P < .001) were observed in the second biopsy, in comparison with the first.

Table 2. Distribution of Histological Activity Scores at the Two Liver Biopsies
 First Biopsy (N = 40)Second Biopsy (N = 40)
  1. NOTE. Data are presented as frequencies (%).

Stage/fibrosis score  
 F07 (17.5)3 (7.5)
 F132 (80.0)23 (57.5)
 F21 (2.5)9 (22.5)
 F30 (0)5 (12.5)
 F40 (0)0 (0)
Grade/activity score  
 A08 (5.0)0 (0)
 A121 (52.5)19 (47.5)
 A211 (27.5)18 (45.0)
 A30 (0)3 (7.5)

At the first biopsy, microvacuolar and macrovacuolar steatosis was absent in 25 cases, grade 1 (<33% of hepatocytes affected) in 13, and grade 2 (33%–66% of hepatocytes affected) in 2. At the second biopsy, steatosis was absent in 27 cases and grade 1 in 13. The grading of steatosis did not change in 34 cases, worsened in one, and improved in five.

Factors Associated With Progression of Fibrosis.

Factors possibly associated with the development of significant fibrosis at the time of the second biopsy were determined by comparing data from patients with no or minimal fibrosis (METAVIR fibrosis score F0-F1; n = 26) with data from patients who had fibrosis scores F2 to F3 (n = 14). Table 3 presents the relative risk, confidence bounds, and P values (by Fisher's exact test) for possibly confounding variables associated with development of significant fibrosis. In addition, serum concentrations of ALT, aspartate aminotransferase, and GGT, measured at baseline, were similar in patients with significant fibrosis and no or only minimal fibrosis at the second biopsy (data not shown). At multivariate analysis, performed among those variables with P < .10 at univariate analysis, a history of excess alcohol consumption (improvement of chi-square 5.70, P < .017) and a high viral load (improvement of chi-square 5.34, P = .021) were the only independent predictors of fibrosis progression. All 10 patients with a history of excess ethanol consumption had a one-point increase or more in the METAVIR fibrosis score, and elevation of serum GGT concentration above the normal range (although still ≤1.5 times the upper normal limit) at the time of the second biopsy was significantly associated with final fibrosis score F2 or greater (7/11 vs. 7/29, P = .029).

Table 3. Univariate Analysis for Possibly Confounding Variables Associated With Progression to Significant Fibrosis (METAVIR F2 or Greater at the Second Liver Biopsy)
ParametersMETAVIR Fibrosis Stage F2-F3 RR (95% CI)P
  • *

    >20 g/d.

  • At the first liver biopsy.

Age (>45 vs. ≤45 years)1.47 (0.64–3.46).510
Sex (male vs. female)0.61 (0.26–1.42).327
Body mass index (>24 vs. ≤24 kg/m2)2.80 (1.17–3.67).043
Excess ethanol* in the past (yes vs. no)4.00 (1.88–6.11).001
Viral load (>8.0 vs. ≤8.0 × 106 copies/mL)3.34 (1.45–7.25).007
Viral genotype (1–4 vs. 2–3)1.25 (0.53–2.76).736
Interval between biopsies (>80 vs. ≤80 months)1.67 (0.72–3.64).310
Initial activity score (A2 vs. A0–A1)9.67 (4.49–9.67)<.001
Initial fibrosis score (F1–F2 vs. F0)∞ (1.14–∞).075
Initial grading of steatosis (grades 1–2 vs. 0)2.22 (0.97–4.90).089
ALT ever exceeding normal range (yes vs. no)2.20 (0.83–6.77).177

Four patients had a two-point increase in the METAVIR fibrosis score: 3 of 4 of these patients versus 7 of 36 of the remaining patients had consumed excess alcohol (>20 g/d) in the past (relative risk = 9.00; 95% CI, 1.41–61.22; P = .042). No other significant associations were found.

Accuracy and Inter-rater Agreement of Noninvasive Methods of Fibrosis Detection.

Both FibroTest and Fibroscan were performed within a maximum of 9 months from the second biopsy (median, 6 months). In Fig. 1, individual FibroTest results (upper panel) and liver stiffness values by Fibroscan (lower panel) are plotted against METAVIR fibrosis scores at the second liver biopsy. In identifying patients with significant fibrosis (METAVIR F2 or F3), choosing the previously reported cutoff values of 8.7 and 9.6 kPa,9 the agreement between Fibroscan and liver biopsy was excellent, with perfect concordance of results (weighted kappa = 1.0). In contrast, the agreement between FibroTest and METAVIR to identify patients with negligible fibrosis (METAVIR F0–F1), choosing the cutoff value (0.31) suggested by the FibroTest manufacturer, was poor (weighted kappa = −0.041). Specifically, 26 (100%) of 26 of the patients for whom antiviral treatment is likely to be postponed (i.e., those with a METAVIR fibrosis scores F0–F1) could have been spared a liver biopsy by performing 1-dimensional transient elastography, in comparison with only 10 (38%) of 26 by FibroTest. Furthermore, without the need for a liver biopsy, 14 (100%) of 14 of the patients eligible for antiviral treatment (i.e., those with a METAVIR fibrosis score F2 or greater) could have been identified by means of the Fibroscan, in comparison with 9 (64%) of 14 identifiable by means of the FibroTest: Fibroscan would have also provided a correct estimate of patients with extensive fibrosis (METAVIR F3). Table 4 shows sensitivity, specificity, and accuracy for both FibroTest and Fibroscan in the study population.

thumbnail image

Figure 1. Scatterplot of individual METAVIR scores in relationship to the results of FibroTest (open circles, upper panel) and Fibroscan (solid circles, lower panel).

Download figure to PowerPoint

Table 4. Diagnostic Value of FibroTest and Fibroscan in Detecting Patients With Significant Fibrosis (METAVIR Fibrosis Score F2 or Greater)
  • *

    Youden index.

Optimal cutoff8.740.31
Sensitivity (%)10064
Specificity (%)10031
Accuracy* (%)10043
Positive predictive value (%)10033
Negative predictive value (%)10062


  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References

The current study documents that, in the evaluation of HCV carriers with NALT, Fibroscan has a far better correlation with liver biopsy than FibroTest. Obviously, this finding does not prove that Fibroscan is a perfect tool to estimate liver fibrosis, only that it matches perfectly with sampling errors inherent with liver biopsies.

Estimation of liver fibrosis by FibroTest and Fibroscan stems from very different premises. The 5 parameters used to perform FibroTest were chosen by logistic regression operated on a selection of basic serum biochemical markers, having histological staging as the independent variable.7 The original database for this study included 339 patients with biopsy-proven hepatitis C, 40% of whom with significant fibrosis. Mean ALT values were thrice the upper limit of the reference range for males, and only 13% of the studied patients had ALT within the normal range. Because biochemical markers were measured once, on the day of biopsy, and during the course of HCV infection ALT fluctuate widely, it is likely that only a few, if any, were true HCV carriers with NALT. Besides, in a subsequent FibroTest prospective validation study, participants needed documented elevated serum ALT levels (at least 1.5 times the upper limit of normal) on three occasions within 6 months before enrollment.8 It is conceivable that these specifics might affect FibroTest performance when applied to HCV carriers with NALT, and that, for FibroTest to be a more reliable method to assess fibrosis in this category of patients, the database should be expanded to include more subjects with their characteristics.

In contrast, Fibroscan infers liver fibrosis by direct measurement of liver elasticity, with which fibrosis is highly correlated. Though intuitively informative in patients with chronic hepatitis, measurement of liver elasticity has been so far precluded by technical limitations and costs. With Fibroscan, however, a transmitted elastic wave can be temporally separated from reflected elastic waves, making the technique comparatively less sensitive to those boundary conditions (including body fat) that would induce artefacts. The acquisition time (typically less than 100 ms) enables measurements to be made on a moving organ such as the liver, and allows a painless, rapid examination with reproducible results,10 at costs highly competitive with respect to biopsy. When applied to patients with biopsy-proven hepatitis C, Fibroscan proved to be a reliable tool to detect significant or extensive fibrosis, with optimal stiffness cutoff values of 8.7 and 9.6 kPa for F ≥ 2 and F ≥ 3, respectively.9 Using exactly the same cutoff values, the current study documents even better sensitivity and specificity values when Fibroscan is used in HCV carriers with NALT. The diagnostic accuracy might be overestimated in the current study, in which sample size is substantially smaller; however, one of the reasons why Fibroscan, in our hands, performed so well, might be that the patients we studied were leaner (having, on average, a BMI approximately 3 kg/m2 lower) than those studied by Ziol et al.,9 none was obese, and just a few were overweight. Lack of body fat might have favored a more accurate measure of liver elasticity, because the fatty thoracic belt attenuates both elastic waves and ultrasound. This favorable situation will probably be applicable to future series including HCV carriers with NALT, who do tend to be lean, because BMI is one major determinant of ALT concentration.16 Thus, Fibroscan might find in this special subgroup of HCV carriers (whose relevance is testified by its frequency, which means costs) its ideal field of application.

If the degree of diagnostic accuracy obtained here by Fibroscan will be confirmed in further studies, the technique is likely to be endorsed by many hepatologists, equally concerned about the low acceptance rate of liver biopsy by patients, who perceive it as an overly aggressive procedure,17 the high costs both of biopsy and antiviral treatment,6 and the risk of missing a diagnosis of advanced liver disease. Would it be possible to identify those patients who, because of an increased risk of developing fibrosis, will need to be monitored at shorter intervals? The current data indicate that for HCV carriers with NALT, a high viral load and a history of excess alcohol consumption are independent predictors of development of significant fibrosis. The relationship between the replication level of HCV and liver damage is controversial,18, 19 although patients with higher viremia might have more intense architectural changes and more severe progression of liver disease than those with lower levels of HCV replication.20 A relationship between heavy alcohol intake and progression to cirrhosis in HCV carriers with NALT is more firmly established,4 and avoidance of alcohol is recommended for all HCV carriers.2 In fact, among them, those who consume alcohol, even within the limits suggested not to be exceeded by international drinking guidelines,15 have increased viremia and hepatic fibrosis.21 Although not detected by testing for carbohydrate-deficient transferrin, those patients in the current study who reported excess alcohol in the past might have been prone to persist in their drinking habits despite medical advice. Although alcohol consumption and viral load might be factors to take into consideration when estimating the risk of fibrosis progression, in clinical practice this will mean that caring physicians, rather than limiting monitoring to specific categories, will have to focus further on patient education. In the absence of a consensus opinion on the amount of alcohol that HCV carriers may be allowed to drink, the current data suggest that it may be safer for caring physicians to recommend these patients suspend any alcohol intake, whether they have elevated transaminases or not, and to reassess this issue at regular intervals.

Until recently, only expectant management and adoption of a healthy lifestyle were recommended for HCV carriers with NALT.22–24 Indeed, in this peculiar subgroup, antiviral treatment was deemed less effective and potentially hazardous, in view of the risk of hepatitis flares.25 Therefore, many authorities in the field believed that for HCV carriers with NALT there was no compelling indication to undergo a liver biopsy. This conservative approach is somewhat challenged nowadays. In fact, the risk of progression to fibrosis in these patients may not be negligible. We report data on a cohort of 40 HCV carriers with NALT, among whom 35% reached significant fibrosis. Although none of the patients had cirrhosis at the end of a median follow-up period of 7.5 years, fibrosis progression was observed in 19 (48%) of 40. In a recent U.S. study, the natural history of a similar cohort of HCV carriers with NALT was compared with the natural history of HCV carriers with elevated transaminases.26 The proportion of HCV carriers with NALT who had significant fibrosis at the end of the follow-up (30%) did not differ from that observed here, but only 22.5% of the American patients had fibrosis progression.26 This discrepancy is puzzling, because the population described in the current paper, having a lower proportion of drinkers, males, and overweight subjects, should have been at lower risk of fibrosis progression. The 2 cohorts might differ with regard to the duration of HCV infection: however, this variable is often difficult to assess (in the current study, a reliable estimate could be obtained in only 6 patients), and mean age is similar. One possible explanation for the higher rate of fibrosis progression in the current study is, of course, sampling error: when paired biopsy samples are analyzed blindly, a 1-stage change in the fibrosis score (−1 to +1), most likely reflecting sampling error or interpreter variability, is easily reported. In our study, all but 1 patient had F0 or F1 at baseline, so most changes in score in the second biopsy could only have occurred in 1 direction. An alternative (or additional) explanation, however, concerns the duration of follow-up, which in the current study was not shorter than 5 years (in comparison to only 2 years in the study by Hui et al.26).

Recently, the opinion that HCV carriers with NALT do not benefit from antiviral treatment has also been challenged. The results of a large, international, multi-center, randomized clinical trial have made it clear that, for HCV carriers with NALT, risks and benefits of an up-to-date combination antiviral regimen are similar to those acknowledged for patients with high ALT.27 Whether antiviral treatment of all HCV carriers with NALT is also cost-effective is questionable, however, because mathematical models estimate that this option results, in patients with mild disease, in relatively high costs for quality-adjusted year of life gained.28 Side effects of treatment are also a concern. Thus, highly motivated patients might undergo “empiric” treatment, particularly when infected by HCV-2 or HCV-3. For the management of the others, deferring therapy to a time when treatments are likely to have become more effective and better tolerated, while giving strong advice on lifestyle issues and monitoring fibrosis non-invasively, could be the most sensible choice.

In conclusion, among HCV carriers with NALT, Fibroscan is superior to the Fibrotest in the noninvasive identification of fibrosis, for which excess alcohol consumption in the past and high viral load represent risk factors.


  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References
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    International drinking guidelines. Washington, DC: International Center for Alcohol Policies; 2003, December. Report No. 14. Available at: Accessed May 17, 2005.
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    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: 110.
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