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Serum Markers for Fibrosis Staging in Chronic HBV and HCV

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Serum Markers for Fibrosis Staging in Chronic HBV and HCV

Discussion


In this study, we validated the diagnostic value of FIB-4 and compared FIB-4 with two other biomarker indices, AST/ALT ratio and APRI. In the training and validation sets, when we compared advanced fibrosis with mild-to-moderate fibrosis (F3–4 vs F0–2) and cirrhosis with lower fibrosis (F4 vs F0–3), we found FIB-4 and APRI to be superior to AST/ALT in both CHC and CHB cohorts. In addition, FIB-4 was a slightly better predictor in the CHC populations but not in the CHB populations.

The present study demonstrates that FIB-4 can predict the upper and lower end of liver fibrosis stage (cirrhosis and F0–F2, respectively) with a high degree of accuracy in both CHB and CHC patients. We found that FIB-4 scores ≤1.58 for CHB and ≤1.21 for CHC accurately predicted mild-to-moderate fibrosis (F0–F2) in both the training and validation sets. In addition, FIB-4 scores >5.17 for CHB and >5.88 for CHC accurately predicted cirrhosis (F4). Thus, the use of FIB-4 could obviate the need for liver biopsy in uncomplicated earlier-stage patients.

Holmberg et al. have discussed several advantages of using FIB-4 and other serum fibrosis markers to initially stage and follow CHC patients. In general, the parameters of these serum markers are easy, rapid and inexpensive to measure. This can be an important factor where more complicated and expensive tests, such as liver biopsy and transient elastography, are less available. More importantly, these markers can be measured in routine clinical care, which makes it easy to monitor patients' disease status over time. As Holmberg et al. pointed out, a non-invasive serum fibrosis marker could avert the challenges in longitudinal monitoring of patients with CHC. In addition, it is possible that a fibrosis marker could be used in conjunction with liver biopsy and transient elastography for successful, individualized and longitudinal disease management because concurring results could provide a higher confidence of predicted fibrosis stage.

There are many other advantages to using FIB-4 in a clinical setting. FIB-4 is based on minimally invasive parameters collected during routine care and thus can be used in primary care settings for ongoing monitoring of CHB and CHC patients at regular intervals for indication that liver fibrosis progression requires further clinical investigation or potential treatment. FIB-4 can also be used when patients are not suitable candidates for FibroScan and cannot or will not undergo biopsy. Use of this parameter can further the clinical research and assessment of large cohorts of viral hepatitis patients for which there is otherwise a lack of means by which to assess liver fibrosis status.

Several studies on prediction of liver disease stage using fibrosis markers among CHB or CHC patients have been published in the past few years. Our study has several unique features. First, the training and validation cohorts used in this analysis were derived from the CHeCS study, which to our knowledge is the first U.S. cohort study to characterize a general population of over 12 000 patients with chronic CHB and CHC infections with both EHR and chart abstraction data collection. In addition, we were able to validate the data. The predictability of different models was consistent between training and validation data set for both CHB and CHC, suggesting that the models were robust. It greatly improves our confidence in model predictions of liver fibrosis stage using FIB-4. The CHeCS study is still ongoing; further validation of FIB-4 and suggested cut-offs on an additional subsequent study cohort are needed.

Secondly, we suggested cut points for classification between F0–F2, F3 (advanced fibrosis) and F4 (cirrhosis). As opposed to previous studies in which the cut points were selected by dichotomizing the five liver stages (either F3–F4 vs. F0–F2 or F4 vs. F0–F3), our cut points were optimized by simultaneously distinguishing the three classes. Our suggested cut points yielded very high prediction accuracies for the lower and upper ends of the liver stages.

Finally, although laboratory results were drawn within 6 months of liver biopsy, our study still confirmed the high predictability of FIB-4 for liver fibrosis stage. In a sensitivity analysis conducted to evaluate the robustness of our findings, laboratory data were collected within a narrower window of liver biopsy (±3 months) and FIB-4 scores were constructed based on these laboratory data. The AUROCs of FIB-4 for predicting advanced fibrosis in the sensitivity analysis were 0.82 (95% CI, 0.76–0.89) and 0.84 (95% CI, 0.84–0.87) in CHB and CHC, respectively (Table S1 http://onlinelibrary.wiley.com/store/10.1111/jvh.12224/asset/supinfo/jvh12224-sup-0001-TableS1-S2.docx?v=1&s=56fb4a8d4d4b43cacc651177ecb3e51d5216cf9f); the AUROCs for cirrhosis were 0.89 for CHB and 0.87 for CHC. Applying the Table 3 cut points to this data, we got prediction accuracy of 87.9% for FIB-4 ≤ 1.58 and 95.0% for FIB-4 > 5.17 for CHB (Table S2 http://onlinelibrary.wiley.com/store/10.1111/jvh.12224/asset/supinfo/jvh12224-sup-0001-TableS1-S2.docx?v=1&s=56fb4a8d4d4b43cacc651177ecb3e51d5216cf9f). The prediction accuracy was 90.9% for FIB-4 ≤ 1.21 and 84.2% for FIB-4 > 5.88 for CHC. Thus, our results are robust using FIB-4 derived from within a 6-month window or 3-month window of liver biopsy. The results were validated in a random subset of the samples.

Limitations to this analysis include variability in these serum markers at various stages of liver disease (fibrosis). Even the 'gold standard', liver biopsy, is subject to sampling error and inter- and intra-observer discrepancies in reading biopsy specimens of 10–20%; thus, cirrhosis could potentially be underdiagnosed up to 20% of the time. However, presumably, roughly equal numbers of patients were mis-categorized by FIB-4 to a higher or lower stage. In addition, although FIB-4 was validated using the internal independent validation set, further evaluation using an external cohort with similar patient characteristics may be useful.

Because FIB-4 is based on parameters that are readily accessible to non-hepatologist clinicians who do not perform liver biopsies but who may wish to care for patients with chronic CHB and CHC infection, this study demonstrates that use of FIB-4 can facilitate monitoring of CHB and CHC patients. Apart from use in a clinical setting, the markers can be easily obtained in longitudinal studies for studying disease progression and treatment effects in a racially diverse large population cohort outside of clinical trials.

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