{'fraction_non_alphanumeric': 0.032027879190175905, 'fraction_numerical': 0.010122801194822437, 'mean_word_length': 5.565359477124183, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Non‐invasive assessment of liver fibrosis: The gap between ideal and real

The past two decades have witnessed a tremendous therapeutic advance in viral hepatitis, spearheaded by antiviral agents, which has resulted in a surge in the number of candidates for starting therapy. Accordingly, recent studies have striven to determine the optimal criteria for selecting patients who can benefit from antiviral treatment, and to decide the optimal starting time of antiviral treatment. This rapid evolution of antiviral treatment in hepatology has inevitably prompted the clinical need for a simple non-invasive diagnosis of liver fibrosis. Liver biopsy (LB) has been the “gold standard” for assessing the severity of necroinflammatory activity and liver fibrosis, but even in expert hands, it is invasive and sometimes associated with rare but serious complications, including bleeding, pneumothorax, and procedure-related death. In addition to sampling error, both intraobserver and interobserver variability can occur in histological interpretation. Despite these pitfalls, LB remains the gold standard due to the absence of better alternatives. Recently, however, many physicians have acknowledged that LB is an imperfect standard and have sought non-invasive serologic fibrosis markers and formulae using demographic and serologic biochemical variables to replace LB. Physicians’ reluctance to perform LB due to potential complications and increasing patient refusal to undergo LB are other reasons for establishing reliable noninvasive serologic fibrosis markers and formulae. Before 2000, serologic fibrosis markers and formulae were in their infancy. More recently, the increasing need for more accurate prediction of liver fibrosis, however, has encouraged a flurry of publications on new non-invasive serologic fibrosis markers and formulae, such as the serum hyaluronic acid level, aspartate aminotransferase (AST)-to-alanine aminotransferase (ALT) ratio, AST-to-platelet ratio index, age–spleen–platelet ratio index, Forn’s test, FibroTest (BioPredictive, Paris, France), FIBROSpect (Prometheus Laboratories, San Diego, CA, USA), HepaScore (Quest Diagnostics, San Juan Capistrano, CA, USA), European Liver Fibrosis Panel score, and the Hui index. Recently, transient elastography (TE) using FibroScan (EchoSens, Paris, France) was introduced as a promising non-invasive device for assessing liver fibrosis, and it has shown considerable accuracy for predicting cirrhosis in patients with chronic viral hepatitis. For a better prediction of liver fibrosis, some studies suggested the combined use of TE, serologic fibrosis markers, and demographic and serologic biochemical variables. In the current issue of the Journal of Gastroenterology and Hepatology, Lee et al. proposed a new fibrosis prediction formula, called the HALF index, which incorporated serum haptoglobin, apolipoprotein A1, a-2 macroglobulin, and TE as constituent variables. The superiority of the HALF index was proved by internal validation. The authors demonstrated that the area under the receiver–operator characteristic curve (AUROC) of the HALF index for predicting significant fibrosis ( F2) was 0.915 (95% confidence interval: 0.868–0.949), which was significantly higher than the AUROC of TE alone (AUROC: 0.877; 95% confidence interval: 0.825–0.918; P = 0.010). However, as the confidence intervals of the HALF index and TE overlap, the statistical significance is questionable. Thus, the clinical applicability of the HALF index needs an independent external validation with a large sample size. In general, most non-invasive serologic fibrosis markers, formulae, and TE or TE-based prediction models are better at predicting liver cirrhosis than “significant fibrosis.” Interestingly, the AUROC of the HALF index for predicting significant fibrosis was higher than that for predicting liver cirrhosis (0.915 vs 0.892) in the study of Lee et al., albeit minimally, whereas the AUROC of TE remained similar (0.877 vs 0.878). In a further analysis, the study population was stratified into two groups according to their serum ALT levels (highand low-ALT groups) to check the influence of necroinflammation on the HALF index, which includes TE as a constituent factor. Importantly, the HALF index was not influenced by a high ALT, whereas the performance of TE increased significantly in the low ALT group, compatible with other reported findings. Conclusively, all these data indicate that the HALF index can predict significant fibrosis accurately, possibly better than TE, free of the influence of a high ALT in causing unreliable estimations of liver fibrosis. Therefore, if the HALF model can be validated sufficiently, it would be a useful tool for detecting significant fibrosis in patients with chronic viral hepatitis and for deciding when to start antiviral treatment. When we interpret the results of cross-sectional studies on noninvasive fibrosis prediction models, several issues should be considered. First, although most studies that assessed the performance of non-invasive fibrosis prediction models, including the study by Lee et al., have used histological fibrosis grade as the standard for comparison, we should be aware of an important question regarding the discrepancy between the interpretation of LB and non-invasive fibrosis prediction models. The histological grading system generally concentrates on the architectural changes in the liver parenchyma due to fibrosis progression, whereas noninvasive fibrosis prediction models seem to be related to the total amount of fibrosis. Thus, it can introduce a different bias to compare them directly. Second, nearly all of the studies of the non-invasive prediction of liver fibrosis have been cross-sectional, and their performance is reported using the AUROC for significant fibrosis or cirrhosis, with corresponding cut-off liver stiffness values and diagnostic indices, including sensitivity, specificity, and positive and Accepted for publication 23 February 2011.