Non-invasive liver disease assessments: can they replace liver biopsy?

Chronic liver disease (CLD) is a significant global health concern and has become one of the leading causes of death worldwide. CLDs can be caused by various factors, including excessive alcohol consumption, obesity and metabolic disorders, autoimmune hepatitis, and viral infections (HBV and HCV) (1). Of these, non-alcoholic fatty liver disease (NAFLD) is the most common, accounting for more than 50% of cases. NAFLD is characterized by the accumulation of lipids in liver cells and is often associated with a number of metabolic problems, including obesity, diabetes, dyslipidemia, hypertension and insulin resistance (2). NAFLD encompasses a spectrum of liver conditions ranging from simple fat accumulation to progressive non-alcoholic steatohepatitis (NASH), a more serious condition involving inflammation and further liver cell damage that can eventually lead to cirrhosis.

The introduction of new terminology for NAFLD, specifically metabolic dysfunction-associated fatty liver disease (MAFLD) and more recently metabolic dysfunction-associated steatotic liver disease (MASLD), has sparked a discussion about whether these terms can be used interchangeably (3). Similar to NAFLD and NASH, the spectrum of MAFLD/MASLD encompasses a continuum from simple steatosis to metabolic-associated steatohepatitis (MASH), a more advanced form of the disease that can progress to fibrosis and, in more severe cases, cirrhosis and hepatocellular carcinoma. A clear understanding of the diagnosis and evolution of MASLD and the other CLDs is critical to improving patient care and treatment strategies.

Currently, liver biopsy remains the gold standard for the diagnosis of fibrosis. However, due to its limitations, including inter- and intra-observer variability, as well as the potential risks and complications associated with the procedure, liver biopsy is not a cost-effective or practical method for screening and risk stratification in patients with CLDs (4), especially considering the large number of at-risk individuals. Over the past few decades, a number of non-invasive tests, known as non-invasive liver disease assessments (NILDAs), have been developed to assess the presence and severity of liver fibrosis (F), steatosis (S) and portal hypertension. NILDAs can generally be divided into two categories: blood-based tests and imaging-based tests. Imaging-based tests are not the subject of this discussion. Blood-based biomarkers were initially developed for HCV, but to date many of these tests have been adapted to assess fibrosis in most of CLDs. The algorithms for these tests are typically divided into three categories:

• Simple, nonproprietary models using routine blood tests.
• Models that combine routine tests with clinical variables such as age, sex, body mass index (BMI), and the presence of diabetes.
• More complex proprietary models that incorporate direct measurements of collagen synthesis or degradation (e.g., hyaluronic acid, procollagen peptides, matrix metalloproteinases, and other proteins) with or without clinical variables.

To date, there are no clear guidelines on how to use these diagnostic tools in the different CLDs in both adult and pediatric patients. The most commonly used tests, because they are easier to find in clinical practice, are those that combine laboratory data with clinical variables; among these, the most wildly used are the Fibrosis-4 Index (FIB-4), which combines age-transaminases-platelets; aspartate aminotransferase (AST)-to-platelet ratio index (APRI), which combines only transaminases and platelets; and the NAFLD fibrosis score (NFS), which is the most complex and requires the combination of age, BMI, transaminases, platelets, albumin and the presence/absence of diabetes.

The American Association for the Study of Liver Diseases (AASLD) Practice Guideline on blood-based NILDAs of hepatic fibrosis and steatosis by Sterling and colleagues (5) has greatly contributed to providing clarity on the usefulness and ease of use of the blood-based NILDA in patients with CLDs and has attempted to clarify the use of each test depending on the liver pathology present and whether it is an adult or pediatric population (Table 1).

In summary, in adult patients with CLDs, including hepatocellular [HCV, HIV-HCV, HBV, HIV-HBV, NAFLD, and alcohol-associated liver disease (ALD)] or cholestatic [primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC)] diseases, the AASLD recommends the use of a simple blood-based NILDA test to detect significant (F2), advanced fibrosis (F3), or cirrhosis (F4). Specifically, in adult patients with chronic HBV and HCV undergoing fibrosis staging prior to antiviral therapy, the AASLD recommends the use of simple blood-based NILDA tests such as the AST to APRI or the FIB-4, as the initial test to detect significant advanced fibrosis or cirrhosis; in adult patients with NAFLD undergoing fibrosis staging, the AASLD recommends the use of simple blood-based NILDA tests such as FIB-4 to detect advanced fibrosis; in adult patients with alcohol-associated liver disease ALD or chronic cholestatic liver disease undergoing fibrosis staging, there is insufficient evidence to recommend the use of blood-based NILDA for fibrosis staging.

According to the AASLD guidelines, some blood-based biomarker panels are superior to other blood-based biomarker panels for staging liver fibrosis. For example, in patients with chronic HCV who require fibrosis staging, AASLD recommends the use of FIB-4 over complex proprietary tests; in patients with NAFLD, AASLD recommends the use of simple, less expensive and readily available blood-based NILDA tests such as FIB-4 or NFS over complex proprietary tests for the detection of advanced fibrosis.

In addition, in adult patients with CLDs, the combination of two blood-based biomarker panels may be superior to a single panel for staging fibrosis using histopathology as a reference.

However, serial blood-based biomarker panels cannot accurately predict the natural history of progression or regression of fibrosis in response to therapy compared to serial histopathology as a reference. For this reason, the AASLD does not recommend the use of blood-based NILDA tests to track progression, stability, or regression in histologic stage (as determined by biopsy) in CLDs.

Finally, in pediatric CLDs, blood-based biomarkers may be accurate in staging liver fibrosis using histopathology as a reference. Therefore, the AASLD recommends the use of simple, cost-effective, and readily available blood-based NILDAs, such as APRI or FIB-4, for the detection of advanced fibrosis in children.

Because BMI is included in many of the indices, caution should be used when using NILDAs to assess steatosis, especially in patients with higher grades of obesity or in those who have experienced significant weight loss or gain. The poor performance of steatosis scores has been reported in previous studies (6,7) and is probably due to the heavy weighting of BMI and waist circumference measurements in their algorithms, which may bias the overall score when applied to a morbidly obese cohort. In fact, some studies have proposed new cut-offs for steatosis scores in severe obesity and validated them by liver biopsy (8). The AASLD recommends against the use of blood-based NILDA tests to detect and follow the progression of steatosis in all CLDs.

To facilitate the integration of blood-based NILDA into clinical practice, the AASLD Writing Group developed an algorithm to provide clinicians with a simple and accessible decision support tool. This algorithm is based on a summary of the existing evidence for NILDAs and recommends that fibrosis staging begin with simple, non-proprietary blood-based tests such as FIB-4, APRI, and NFS. These tests are preferred because they are widely available and perform well compared to proprietary tests, although proprietary tests may be used where available. Among the three major non-proprietary NILDA tests (FIB-4, APRI and NFS), FIB-4 stands out for its superior performance, particularly in identifying advanced stages of fibrosis. NFS is considered equivalent to FIB-4 in assessing advanced fibrosis only in NAFLD patients.

Although imaging-based NILDA, such as elastography, are in some cases more accurate than blood-based tests (9), they are not being widely applied. As imaging-based NILDA become more accessible in clinical practice, their combined use with blood-based NILDA for clinical decision making is expected to increase. Because blood-based NILDA is not accurate enough to follow fibrosis progression and assess steatosis, the AASLD Writing Committee recommends the use of imaging-based tests, which are more reliable for this purpose.

Conclusions

Over the past 15 years, the introduction of various non-invasive methods to assess the fibrogenic progression of CLD has significantly changed clinical practice. These advances have not only facilitated earlier detection of hepatic fibrosis, but also introduced new models for stratification, prognosis, and treatment of patients with CLD (10). Available tools for non-invasive assessment of fibrosis range from simple scores based on routine laboratory tests to more complex serum biomarkers that measure circulating components involved in extracellular matrix accumulation and remodeling during fibrosis. In addition, elastography techniques to assess liver stiffness have not been fully exploited.

The primary goal of these methods is to overcome the limitations of liver biopsy/histology and hepatic venous pressure gradient (HVPG) measurement, reducing the need for these invasive procedures. NILDAs have become central to the assessment of liver disease severity and may replace liver biopsy as a diagnostic tool in many clinical scenarios.

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-2024-658/coif). The authors have no conflicts of interest to declare.

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