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In Gut, Loomba and Adams refer to the recent advances in non-invasive assessment of hepatic fibrosis.1 Not surprisingly, many recent studies in the field were conducted in patients at risk or with clinically diagnosed non-alcoholic fatty liver disease (NAFLD). The implications of non-invasive testing are particularly far reaching in this group of patients since this disease affects 25% of Western populations. The principal need to identify the small subset of NAFLD patients at-risk of progressive disease and liver-related outcomes is obvious.
Recent retrospective longitudinal studies have shown that non-alcoholic steatohepatitis (NASH) is not an independent predictor of liver-related complication or mortality in NAFLD.2 3 NASH is a risk factor of fibrosis progression rather than an immediate risk of liver related complication and therefore positions at a lower prognostic significance in the hierarchical model of NAFLD.4 The diagnosis of NASH still requires a liver biopsy, a procedure not suitable for the very large NAFLD population because it is invasive and not widely accepted among non-specialised physicians and patients. No non-invasive test (NIT) has so far achieved enough accuracy and validation for the non-invasive diagnosis of NASH. One explanation is that most of the known candidate blood markers for NASH are not specific of the liver and could be produced by other organs, especially the expanded adipose tissue observed in NAFLD. Moreover, liver biopsy results are limited by a fairly high discordance rate on particular features, particularly the presence of hepatocyte ballooning, which leads to a modest negative predictive value of a single biopsy for the diagnosis of NASH.5 Finally, NASH corresponds to a composite endpoint combining different liver lesions, which multiplies the risk of discrepancies between pathologists and thus impairs the external validation of NITs developed for this diagnostic target. The non-invasive diagnosis of NASH is thus a real challenge, and strong efforts are currently developed through large consortia (LITMUS in Europe, NIMBLE in USA) with the hope to find and validate new biomarkers able to accurately diagnose this condition.
On the opposite, liver fibrosis is the only liver lesion independently associated with long-term overall mortality, liver transplantation and liver-related events in NAFLD.2 3 Liver fibrosis evaluation on liver biopsy shows very good reproducibility among pathologists.6 7 Several NITs, essentially elastography devices and blood tests, are now available for the evaluation of liver fibrosis in NAFLD. In their paper, Loomba and Adams provide a complete and comprehensive overview of the different benefits of these tests for clinical practice.1 Investigating a larger region of interest compared with the volume of a liver biopsy, elastometry procedures offer obvious advantages. NITs have good accuracy for the diagnosis of advanced F3-4 fibrosis8 and therefore can identify the subset of patients with NAFLD who have an impaired liver-related prognosis and who therefore require an intensive management of their liver disease. The non-invasive diagnosis of advanced fibrosis can be further improved and achieve excellent accuracy through the combination of NITs, with sequential approaches having the added advantage of defining a patient pathway between primary care or diabetologists and liver specialists.8 NITs of fibrosis show excellent area under the receiver operating characteristics (AUROCs) for the diagnosis of cirrhosis,8 which is also an important condition to diagnose as its presence requires the biannual screening of hepatocellular carcinoma. However, work is still required to better define the cut-offs and the practical rules for the diagnosis of cirrhosis with NITs in NAFLD. New NITs have been recently developed to stratify the risk of hepatocellular carcinoma, such as the GALAD score.9 This approach will be very helpful to optimise the screening of hepatocellular carcinoma which can occur outside cirrhosis in NAFLD. Finally, going back to the prognostic significance of liver fibrosis stages, longitudinal retrospective prognostic studies have demonstrated that NITs calibrated on liver fibrosis are themselves prognostic markers able to stratify the risk of liver-related outcomes and mortality in NAFLD.10 11 This new concept reinforces the relevance of using NITs instead of liver biopsy for the management of patients with NAFLD in clinical practice.
Most of the phase IIb and phase III therapeutic trials currently ongoing in NAFLD include patients with an active disease (NASH and NAFLD Activity Score ≥4) and a significant amount of liver fibrosis (F2-F3 fibrosis stages). Such ‘fibrotic NASH’ adds an earlier stratum in the hierarchical model of NAFLD and is becoming an important condition to diagnose. Indeed, beyond the current patient selection for therapeutic trials, it will correspond to the indication of the new treatments in clinical practice once the new drugs will be approved. As previously said, we have no NIT for the diagnosis of NASH, and those available for fibrosis are accurate for advanced F3-F4 but much less for earlier fibrosis stages.7 To address this unmet need, new NITs have been recently developed for the non-invasive diagnosis of fibrotic NASH such as the blood tests MACK-3 and NIS4, and the elastographic test FAST.7 12 All these tests show good accuracy for fibrotic NASH with AUROC around 0.80–0.85 in the derivation and validation studies, demonstrating that it is possible to non-invasively diagnose relevant earlier stages within the NAFLD spectrum.
The available NITs calibrated on the different fibrosis stages allow full non-invasive stratification of NAFLD that is well adapted to decision-making in clinical practice (figure 1). However, there is still a place for liver biopsy in NAFLD, mainly if the result is likely to alter the patient management: doubt about another cause of chronic liver disease that may benefit from treatment, doubt about cirrhosis despite a well-conducted non-invasive testing or willingness of the patient to participate in a therapeutic trial. Currently, the presence of NASH alone has little influence on the patient management and therefore should not in itself represent an indication for liver biopsy. Nevertheless, for the future, research on NASH biomarkers needs to be supported, especially to facilitate the evaluation of NASH resolution if further validated as a relevant surrogate endpoint in NAFLD. On the other hand, liver fibrosis is a highly relevant condition to diagnose as it defines the subset of patients with NAFLD in need for specific intervention and cancer surveillance. This important point leads to individualise the two distinctive categories of ‘fibrotic NAFLD’ and ‘non-fibrotic NAFLD’ (figure 1). Thanks to the NITs available, this concept of ‘fibrotic NAFLD’ offers a practical solution with no need for histology to define at-risk NAFLD patients who need a specialised management of their liver disease.
Contributors Both authors have written the manuscript and drawn the figure together.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Commissioned; externally peer reviewed.
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