Serologic noninvasive liver disease assessments: clinical utility and future potential

Chronic liver disease (CLD) is prevalent in the United States and globally. It is a major source of mortality and morbidity with loss of productivity due to disability (1). Recent advances in the treatment of hepatitis C virus (HCV) infection has led to some reduction in cirrhosis development from this etiology, however, increasing rates of alcohol use and metabolic dysfunction associated liver disease (MASLD) threaten to counter this progress (1). The progression of CLD to cirrhosis and its subsequent squeal—complications of portal hypertension such as esophageal varices, hepatic encephalopathy, and hepatocellular carcinoma (HCC)—accounts for much of the mortality and morbidity in patients with cirrhosis (2). For all these reasons, assessing patients with CLD for significant fibrosis is essential for early intervention to slow progression and reduce the incidence of these serious complications.

Liver biopsy remains the gold standard for assessing liver parenchymal disease (3). It enables direct histopathologic characterization of stage of CLD, covering a variety of potential causes, including metabolic, infectious, and alcohol-related liver disease. In conjunction with histological scoring systems such as METAVIR, Ishak, and Batts-Ludwig, liver biopsy can stage CLD and guide appropriate management of the patient’s specific liver disease (3). Despite its utility, liver biopsy has limitations such as its invasive nature, cost and associated risk of hemorrhage. In addition, it provides information regarding only the specific area sampled and interpreter bias with vulnerability in result (3). For these reasons, liver biopsy requires a significant clinical indication to perform and has a relatively higher threshold for use compared to other noninvasive methods of evaluating liver disease.

The emergence of noninvasive liver disease assessment (NILDA) techniques has transformed patient care by reducing the need for invasive procedures like liver biopsy. NILDA methods are broadly categorized into imaging-based and blood-based approaches. The article by Sterling et al. provides guidance for healthcare providers in using these tests to manage patients with liver fibrosis and steatosis (4). Due to the heterogeneous spectrum of liver disease due to many possible causative etiologies, the authors stratified their recommendations based upon the underlying etiology of CLD.

According to the American Association for the Study of Liver Diseases (AASLD) guidelines, several imaging and serological tests may be used to assess the severity of liver fibrosis and guide the need for biopsy. One of the most used is the Fibrosis-4 (FIB-4) index, which enables the serological tracking of fibrosis over time using age, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelet count (4). This tool has demonstrated acceptable accuracy in differentiating between Ishak scores 0–3 and 4–6 [area under the receiver operating characteristic curve (AUROC) 0.765] and can exclude advanced fibrosis with a positive predictive value and specificity of 65% and 97%, respectively, for a cutoff greater than 3.25 (5). Subsequent reviews of the FIB-4 index have confirmed its external validity in reducing the need for biopsy in patients with chronic hepatitis B (CHB) infection (6), though other studies have noted a decreased predictive value with advancing patient age (7).

Despite improving treatment and vaccinations, hepatitis B virus (HBV) and HCV remain common causes of hepatic fibrosis worldwide. In the current era of direct-acting antivirals (DAAs) for HCV, detecting advanced fibrosis (F3/4) or cirrhosis is prioritized over early-stage fibrosis (F0/1), with ongoing HCC surveillance recommended for advanced cases post-treatment. Simple biomarkers like AST to platelet ratio index (APRI) and FIB-4 are widely used but can yield indeterminate results, while proprietary tests such as FibroTest^® (branded FibroSURE^® in the United States) have shown moderate diagnostic utility for fibrosis staging in HCV (4). Additionally, studies have shown that baseline FibroSURE^® scores were lower in patients with a sustained virological response (SVR), and scores declined further with successful therapy, suggesting these markers may reflect reduced fibrogenesis in patients responding to antiviral treatment (8). Post-SVR, biomarker thresholds may underestimate advanced fibrosis, and validation of these markers remains necessary. For HBV, fibrosis staging is combined with disease activity measures like HBV DNA and ALT, though blood-based biomarkers like APRI and FIB-4 are less routinely used, given limitations in sensitivity. Additionally, some studies have shown that while FibroSURE^® has significant negative predictive value in excluding cirrhosis in CHB, it is insufficient in its diagnosis (9). However, other studies find that positive predictive value may improve when used in combination with AST (10). Fibrosis in children with HBV or HCV is rare and difficult to assess with these markers, which show variable accuracy compared to adults. Larger studies are needed to establish reliable biomarker thresholds for fibrosis assessment and disease progression in both HCV and HBV, particularly in pediatric patients.

Another tool used to assess the need for biopsy is the NAFLD fibrosis score (NFS), which is more comprehensive and includes age, body mass index (BMI), diabetes or glycemic dysregulation, AST, ALT, platelet count, and albumin. The NFS has shown utility in distinguishing between metabolic dysfunction-associated fatty liver disease (MAFLD) patients with and without advanced fibrosis, avoiding biopsy in 75% of cases, with a positive predictive value of up to 90% (11).

The AASLD guidelines recommend no biopsy for patients with a METAVIR score of F0/F1, defined by a FIB-4 score <1.45 in non-MAFLD patients and FIB-4 <1.3 or NFS <−1.455 in MAFLD patients. Biopsy should be considered for non-MAFLD patients with a FIB-4 score >3.25 and for MAFLD patients with FIB-4 >2.67 or NFS >0.676, as these scores suggest a METAVIR score of F3/F4. Scores between the cutoffs above are considered indeterminate and may benefit from non-invasive imaging modalities such as transient elastography to further assess fibrosis and need for biopsy (4).

The AASLD guidelines did not make a recommendation regarding use of blood-based NILDA for assessing fibrosis in patients with alcoholic liver disease, citing limited available evidence to support a recommendation (4). Of the few published studies reviewing serologic NILDAs compared to liver biopsy, some have noted the utility of serologic NILDA in ruling/out clinically significant liver fibrosis with enhanced liver fibrosis (ELF) score compared to other proprietary and non-proprietary NILDAs. ELF combines measurements of procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinase-1 and hyaluronic acid to create score for assessment of liver fibrosis (12). One systematic review found that the AUROC of ELF was consistently greater than 0.9 across the 3 studies reviewed (13). Another Cohort study compared ELF to liver biopsy for patients with alcohol related liver disease and non-alcohol related liver disease (mostly hepatitis C related CLD) and found ELF to be non-inferior to liver biopsy in the identification of advanced fibrosis and cirrhosis (12). This study also found that ELF had potential utility for prognostication of alcohol related CLD for development of liver related events such as complications of portal hypertension, liver transplantation, HCC, or death (12). These findings suggest that there is considerable promise in serologic NILDA for alcohol related CLD and that more investigation in this area would be needed to further elucidate their utility.

Serologic NILDAs also have several inherent limitations that influence their clinical utility. Namely the influence of confounding variables on the individually measured components of these serologic scoring systems, such as dynamic changes related to systemic inflammation or metabolic syndrome (14). Another consideration, as previously mentioned in regard to simple indirect serologic NILDAs, is the indeterminant ranges wherein the scores are not able to discern moderate amounts of fibrosis without additional validation with repeat serologic NILDA or using an imaging-based modality. Another consideration is access to proprietary serologic NILDAs that measure direct markers of fibrinogenesis is not equal across the United States and the world, with access focused on centers with more resources (14). These factors are important to consider as we look to incorporate serologic NILDAs into clinical practice.

In summary, patients with CLD are at risk for progression to cirrhosis, and the multiple complications that can predispose patients to, if not identified in a timely manner and managed accordingly. As it stands, the gold standard for grading CLD has been based on histopathological scoring of fibrosis and steatosis using invasive liver biopsies. NILDA presents a unique opportunity to identify these patients before they become decompensated or develop acute illness from their CLD and thus allow for timely intervention. Image- and serology-based NILDA are available for use in patients in the United States to varying degrees and have differing utility for the various etiologies of CLD. More research is needed to refine their role in clinical care of patients with CLD.

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: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2024-661/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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