Getting persuasive about the non-invasive: assessing liver fibrosis in practice—without a biopsy

Chronic liver disease (CLD) is the 10th leading cause of death in the United States (1,2). The early detection of liver fibrosis is crucial in minimizing disease progression and risk of death (2). While the gold standard for diagnosis is liver biopsy, it is invasive, costly, and less accessible than non-invasive fibrosis assessment tools which utilize blood work and/or imaging (2,3). The growing prevalence of CLD emphasizes the importance of noninvasive liver disease assessments (NILDA), with the availability of blood base and imaging assessments (3).

Sterling et al. (2) provided clinical guidance on the application of NILDA. The authors recommend that all CLD patients undergo combined blood-based and imaging-based NILDA for the detection of fibrosis. The data behind which combination of blood or imaging-based NILDA should be used in different patient populations and clinical situations requires further study. The authors also highlight that NILDA are applicable in pediatric populations, which is important given the growing burden of metabolic-associated steatotic liver disease in this age group (4). Sterling et al. are commended in utilizing a generalized assessment scoring system for fibrosis and steatosis, rather than individualized by disease etiology. Given the frequency at which mixed-etiology or overlapping liver diseases are seen, this is a worthwhile simplification.

One of the aspects that make noninvasive diagnostic measures more favorable in comparison to liver biopsy is the cost-effectiveness aspect. Fierbinteanu Braticevici et al., when comparing liver biopsy to serum markers, found that liver biopsy was $2,200 versus the standard laboratory cost for the serum markers (5). However, other sources state it could cost between $900–1,200 (6). Regardless, this could be costly for patients, especially if this was to be performed routinely. Although imaging studies are not touched upon, it does highlight the discrepancy between biopsy and NILDA.

Congly et al. found in a study focusing on non-alcoholic fatty liver disease (NAFLD) diagnosis using 2D ultrasound shear wave elastography (2D-US SWE), transient elastography, NAFLD fibrosis score, and Fibrosis-4 (FIB-4) found that the best approach for the accuracy and cost-effectiveness was with a two-step risk strategy (7). Starting with initial stratification with FIB-4 or NAFLD fibrosis score and further evaluating for fibrosis using elastography (7). In this study, an important endpoint was the cost per correct diagnosis (7). They found that for significant fibrosis (> F2), FIB-4/SWE cost $148.75/correct diagnosis, and SWE cost $276.42/correct diagnosis, which correctly identified 84% of patients (7). For advanced fibrosis (> F3), FIB-4/SWE correctly identified 92% of patients (7). When stratifying for alanine aminotransferase (ALT) (normal versus abnormal), they found that the costs/diagnosis for advanced fibrosis were less in the normal ALT group (7). This further supports the measures put forth by Sterling et al. that noninvasive measures, especially when utilizing a combination of blood-based testing and imaging testing, are superior to liver biopsy when considering the cost-benefit for patients.

Liver biopsy has multiple known risks. Pain is experienced in 84% of patients and hemorrhage in 11% of patients (8). As it is an invasive procedure, it does carry the potential for fatal bleeding of 0.001–0.2% (8). Moreover, for an accurate diagnosis of fibrosis, the specimen needs to contain enough portal tracts and not be fragmented (8). Prior studies have suggested that up to 25% of biopsy samples are insufficient in one of these facets (6,8). Additionally, liver fibrosis can occur in an unequal distribution through the liver, which is suboptimal if the biopsy sample is not obtained randomly (5). While it is a valuable tool for diagnosis, it only gives a snapshot of the fibrosis stage at that time (6). For proper monitoring, repeat assessments need to be done, which is more feasible with imaging studies.

Liver stiffness measurement (LSM) by elastography can be elicited by ultrasound (US) or magnetic resonance elastography (MRE) (2,8). Both are excellent options for staging of fibrosis (2,8). MRE has been shown to have a higher accuracy especially in those who are obese; however, US is more widely available and less expensive than MRE (8). US, while more widely accessible, are not without limitations, such as technical aptitude, patient body habitus, and artifact on imaging (8). However, the authors highlight the sparse number of studies that have compared US versus MRE directly, although this would be an important area for future study.

Although there are numerous benefits of NILDA, there are several factors that need to be considered. First, NILDA are not accurate for certain etiologies of CLD, such as congestive hepatopathy, hemochromatosis, or congenital diseases such as biliary atresia, Fontan-associated liver disease, among others, where standardized reference ranges for elastography do not exist, and fibrosis is likely to be overestimated. Second, obtaining accurate windows can be difficult in obese patients or those with significant truncal adiposity. Finally, transient and MRE is less accessible in resource-limited settings.

Despite these limitations, the statements put forth by Sterling et al. in these guidelines is a step forward in the application of NILDA in clinical practice to accurately define CLD so care and subsequent health outcomes can be optimized, with an important lens on the prioritization of testing that will minimize cost and improve accessibility.

Future efforts should include gaining a clearer understanding of applying NILDA in practice, especially given variations in the progression of liver fibrosis based on etiology of liver disease, along with medical comorbidities that could accelerate the natural history of liver disease. Another area of interest is the role of longitudinal surveillance for CLD complications such as hepatocellular carcinoma in patients with advanced fibrosis (F3). This is a commonly encountered situation in clinical practice, but the risk/benefit of screening and cost utilization should be evaluated.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-445/coif). The authors have no conflicts of interest to declare.

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