Can aspartate aminotransferase to platelet ratio index replace liver biopsy in chronic hepatitis C?

More than 170 million people are chronically infected with hepatitis C virus (HCV) worldwide. Patients with chronic HCV may develop decompensated liver disease and hepatocellular carcinoma. This risk is highest in patients with advanced fibrosis.[1]

The knowledge of stage of liver fibrosis is essential for prognostication and decisions on antiviral treatment. [2,3] Chronic hepatitis C (CHC) patients with no or minimal fibrosis at presentation, appear to progress slowly and treatment could possibly be delayed or withheld. On the other hand, patients with significant fibrosis (i.e. septal or bridging fibrosis) progress almost invariably to cirrhosis over a 10-20 years period, thus antiviral treatment is strongly recommended.[4,5]

Liver biopsy is currently the gold standard in assessing liver histology. Although percutaneous liver biopsy is generally a safe procedure, it is expensive and does carry a small risk for complication. Furthermore, liver biopsy is an invasive procedure, prone to sampling error and has the potential for medical complications. Inter- and intra-observer discrepancies of 10 - 20% have been reported in assessing hepatic fibrosis and may lead to erroneous estimation of cirrhosis. [6,7,8]

Many studies have been undertaken to evaluate the use of readily available laboratory tests to predict significant fibrosis or cirrhosis in patients with CHC. [9,10,11,12] Wai et al concluded from their study that a simple index, the APRI, consisting of 2 readily available laboratory results (AST levels and platelet count), can predict significant fibrosis and cirrhosis in treatment-naïve CHC patients with a high degree of accuracy.[13]

In this study we tried to evaluate the accuracy of the readily available laboratory tests (aminotransferases, platelet count and APRI) in diagnosing liver fibrosis in treatment-naïve CHC patients. Keeping liver biopsy as the gold standard, we also compared the accuracy of correlation between the results of simple lab tests and liver biopsy, with the degree of liver fibrosis predicted by them.

Methods

Patient selection

This study was conducted on 113 pediatric and adult patients suffering from CHC. The diagnosis of CHC was established by the presence of HCV antibody on ELISA and confirmed by the presence of HCV RNA using qualitative polymerase chain reaction assays. Patients with the following conditions were excluded from the study: co-infection with HBV or HIV, coagulopathy or thrombocytopenia to a degree which precludes the safe performance of percutaneous liver biopsy, previously treated HCV infection, biopsies less than 10 mm long and biopsies including less than 5 portal tracts to verify for expanded portal tracts with fewer CD4 cells and more CD8 cells. [14]

Demographic and clinical information of the patients including, age, sex, laboratory results and liver biopsies reports were obtained from their medical records.

Laboratory results performed within 2 weeks from the date of liver biopsy were used for analysis. If more than one set of laboratory test results were available, the results closest to the time of biopsy were used.

Results of serum aminotransferase (ALT, AST) levels were expressed as ratio of the upper limit of normal (ULN; which was 49 U/L for both ALT and AST). The AST to platelet ratio index (APRI) was calculated according to the following equation devised by Wai et al: [13]

             AST level (/ULN)
APRI = ––––––––––––––    X 100
            Platelet count (109/L)

Informed written consent was taken from parents of pediatric patients and from adult patients before liver biopsy. The procedure was performed as an outpatient procedure, using a lateral intercostal approach for all patients. We used the percussion technique, [15] using a 1.6 mm diameter modified Menghini (secure cut) biopsy needle (Hospital Service S.P.A. Via Naro, 91-00040 Pomezia (RM) Italia).

Histopathology slides of all eligible patients were retrieved. All biopsies were reviewed by a single pathologist, who had no knowledge of the clinical characteristics of any of the subjects.

The grade of activity and stage of fibrosis were scored as per published METAVIR criteria, [16] assigning a score of 0 to 4, where F0 = no fibrosis, F1 = portal fibrosis without septa, F2 = portal fibrosis with few septa, F3 = numerous septa without cirrhosis, and F4 = cirrhosis. The study protocol was approved by the local ethics committee of the Cairo University Pediatric Hospital.

Statistical methods

All patient data were tabulated and processed using SPSS v10.0. All patient characteristics were described in numbers and percentage. Spearman correlations were computed between fibrosis score and other laboratory markers (AST, ALT, platelet count and APRI). Receiver operator characteristic curves (ROC) were generated to assess the validity of these markers in diagnosing liver fibrosis reliably in all patients.

Results

The mean age of the 76 pediatric patients was 7.96 ± 4.04 years; 40 (52.6%) were male and 36 (47.4%) females. Twenty eight (36.8%) patients showed no evidence of fibrosis on liver biopsy (METAVIR F0), 26 (34.2%) patients were graded F1, and 22 (29%) as F2. The adult patient group comprised of 37 patients; including 5 (13.5%) females and 32 (86.5%) males, with mean age of 41 ± 10.43 years. Twelve patients (32.4%) were scored F2 and 25 patients (67.6%) as F3-4. The demographic and laboratory characteristics of both groups are shown in Table 1.

On comparison of laboratory data with the degree of fibrosis, we didn’t find any significant difference between the results for children with and without liver fibrosis or for adults with moderate and severe fibrosis (Table 2). Correlation studies between the stages of fibrosis and values of different laboratory markers revealed no significant associations between the two (Table 3).

The area under the receiver operator curve (AUROC) for predicting significant fibrosis in pediatric patients was 0 5 for AST levels, 0.37 for AST/ALT ratio and 0.49 for APRI (p = 0.99, 0.18 and 0.9 respectively) (Figure 1). Likewise, the AUROC for predicting significant fibrosis in adults was 0.59 for AST levels, 0.76 for AST/ALT ratio and 0.63, for APRI (p = 0.5, 0.07 and 0.35 respectively) (Figure 2). As the AUROC was not significant for either of the patient groups, we couldn’t conclude a best cutoff for neither adult ROC nor pediatric curves.

Discussion

In the present study we tried to assess the validity of noninvasive, simple, easily available blood tests to predict significant fibrosis in a consecutive series of treatment-naïve CHC patients. One hundred and thirteen patients suffering from chronic viral hepatitis C were included in this study. They included 76 children [comprising of 28 without any evidence of fibrosis on liver biopsy and 48 showing mild to moderate fibrosis (Metavir score 1-2)]; and 37 adults [comprising of 12 with moderate fibrosis (score 2) on liver biopsy and 35 with severe fibrosis (Metavir score 3-4)].

The AST levels were higher in patients who showed significant liver fibrosis than in patients with insignificant fibrosis, both among pediatric and adult patients; however the difference did not reach statistical significance. Kamimoto et al [17] demonstrated that progression of liver fibrosis may reduce the clearance of AST, leading to increased serum AST levels. In addition, advanced liver disease may be associated with mitochondrial injury, resulting in more marked release of AST, which is predominantly present in mitochondria and cytoplasm, whereas ALT is solely located in the cytoplasm.[18,19] We didn’t find any difference between the AST/ALT ratio in children with hepatic fibrosis and those without fibrosis. Similarly we did not find any significant difference in the AST/ALT ratio in adult patients with moderate and evere hepatic fibrosis. Our study results conform to many precious studies which report that AST/ALT ratio failed to predict the presence of fibrosis or cirrhosis in patients with chronic hepatitis C.[9,10,11]

While some authors have reported that an AST/ALT ratio >1 may suggest the presence of cirrhosis and have demonstrated positive correlation with both histological stage and clinical evaluation, [20,21,22] several others have concluded that an AST/ALT ratio >1 may not be as useful for predicting cirrhosis in chronic hepatitis C. The results of latter support the need for liver biopsy prior to treatment of chronic hepatitis C, since the AST/ALT ratio failed to accurately predict the presence of cirrhosis in their patients.[23,24]

We investigated the relationship between the stage of fibrosis, AST level and platelet count by employing the APRI devised by Wai et al. [13] Although the AUROC curve for predicting significant hepatic fibrosis was much lower in pediatric patients (AUROC 0.49, p = 0.9) than in adult patients (AUROC 0.63, p =0.35), but both failed to reliably predict significant fibrosis in these patient groups.

Bourliere et al [25] reported that noninvasive markers of fibrosis may have different diagnostic accuracy depending on the prevalence of significant fibrosis in the population under study and that a normal AST value can lead to APRI inaccuracy. Chrysanthas et al,[26] Sebastiani et al,[27] Lackner et al,[28] and Pohl et al[11] concluded that simple laboratory tests may render liver biopsy unnecessary only in a minority of patients with CHC but the need for liver biopsy even if reduced, cannot be completely avoided. Al-Mahtab et al[29] concluded from their study that APRI does not appear to be of use in predicting fibrosis in patients with chronic hepatitis B infection. They contended that the probable reason for lack of correlation between APRI and fibrosis in chronic hepatitis B is the platelet count which was not decreased in their group of patients. Shaheen et al30 systematically reviewed studies comparing FibroTest or FibroScan versus biopsy in HCV patients. The authors concluded that FibroTest and FibroScan have excellent utility for the identification of HCV-related cirrhosis, but offer lesser accuracy for early stage disease. They noted that refinements were necessary before these tests could replace liver biopsy.[30] Sporea and colleagues[31] concluded from their study that evaluation of liver fibrosis can be performed both by FibroTest and liver biopsy, the latter being the “gold standard”. They further stated that non-invasive markers of fibrosis may find their utility over the coming years but current recommendations by authorities in the field mandate liver biopsy necessary for the evaluation of chronic hepatitis, despite the fact that it is not a perfect test. On the other hand, numerous studies[32,33,34,35,36,37,38,39] have demonstrated that APRI was a good estimator of hepatic fibrosis in patients with CHC. The usage of different histological scoring systems, inter-observer and/or intraobserver variability and differences in patient populations in these studies could be responsible for this disagreement.

Liver biopsy is considered the most accurate modality to estimate the necro inflammatory activity of a pathological hepatic process and the stage of disease involving the liver, by assessing the type and extent of fibrosis along with the recognition of architectural disturbances. Increase in aminotransferase levels do not adequately reflect the disease severity and assays measuring fibrosis-related bio-molecules circulating in the blood are not yet standardized for wide spread clinical use. [40]

Our study had its limitations. We included only early degree fibrosis cases in the pediatric age group. We also excluded patients with severe coagulopathy or thrombocytopenia that may interfere in performing a safe liver biopsy. Using two different age groups could also affect our results.

In conclusion, the results of our study do not demonstrate any diagnostic role of aspartate aminotransferase to platelet ratio index (APRI) as a simple non-invasive test for diagnosis of liver fibrosis, and liver biopsy remains the gold standard for this purpose. Novel biomarkers of fibrosis are needed for early detection of mild to moderate fibrosis. Acknowledgments The authors thank the patients and their parents for their cooperation during this study.

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