Chronic liver disease affects many millions of people worldwide and is a major cause of premature death. Assessing liver fibrosis in patients with chronic liver disease can determine disease stage and progression, and also response to therapy, but whether this is best performed via a liver biopsy or noninvasive methods is a matter for debate.
Here, two European experts present their opposing viewpoints on how to assess fibrosis in the setting of chronic liver disease.
Biopsy is the reference method for evaluating liver fibrosis and the ‘gold standard’ against which noninvasive methods are compared. The histological stage of fibrosis is one of the most important prognostic factors in patients with chronic liver disease, independent of aetiology. Advanced fibrosis is a strong prognostic factor in alcohol-related liver disease and the most important prognostic indicator in nonalcoholic fatty liver disease (NAFLD), where individual histological fibrosis stages are associated with distinct patient outcomes.
Liver biopsy is the only way to diagnose nonalcoholic steatohepatitis (NASH) and, generally, offers the added value of assessing disease severity, highlighting possible concurrent disease and evaluating fibrosis progression or regression in paired biopsy samples. The known limitations of sampling and interobserver variability are minimized by high-quality biopsy techniques (using ≤16-gauge needles, core length >15 mm) and evaluation by expert hepatopathologists. Recently, digital image analysis and second harmonic generation technology have enabled objective quantitative and qualitative assessment of liver tissue collagen and can highlight subtle differences in fibrosis between biopsy samples.
Noninvasive methods of assessing liver fibrosis are widely used with increasing accuracy for diagnosing the absence of fibrosis or presence of severe fibrosis/cirrhosis and, therefore, are helpful to select patients for liver biopsy. However, noninvasive methods cannot distinguish intermediate stages of fibrosis and some serum marker measurements may reflect fibrotic processes in other organs. Failure of application (2–5%), unreliable results (11–15%) and false-positive results in acute inflammation, cholestasis or liver congestion are known limitations of transient elastography, while the patented serum markers have limited availability. While noninvasive tests reduce the need for liver biopsy for fibrosis evaluation they cannot replace it.
Over the past decade, there has been growing interest in novel noninvasive strategies for the evaluation of fibrosis, given the well-known limitations of taking liver biopsy samples — invasiveness, limited patient acceptance, rare but potentially life threatening complications, sampling variability, pathologist experience, and cost. Taking liver biopsy samples also appears unrealistic considering the magnitude of the nonalcoholic fatty liver disease (NAFLD) epidemic, with around 25% of the general population affected in Western countries.
Noninvasive testing currently relies on two different but complementary approaches: measuring the levels of serum biomarkers and estimating liver stiffness using ultrasound-based elastography techniques, with transient elastography (FibroScanTM) being the pioneer. Although these two approaches are complementary, they are based on different rationales and concepts. Transient elastography measures liver stiffness related to elasticity, which corresponds to a genuine and intrinsic physical property of the liver parenchyma. By contrast, serum biomarkers are combinations of several, not strictly liver-specific, blood parameters that are optimized to predict the stages of fibrosis as assessed by liver biopsy.
The most validated noninvasive biomarker tests are FIB-4, AST to platelet ratio index (APRI), NAFLD fibrosis score (nonproprietary formula) and FibroTestTM (proprietary), while FibroScanTM is the most validated elastography technique. All these tests are better at ruling severe fibrosis-cirrhosis out than ruling it in. They also have prognostic value in the context of cirrhosis. For instance, they are able to identify the subgroup of NAFLD patients at high risk of developing liver-related complications and death. As a result, noninvasive tests are now widely used in routine clinical practice and included in national and international guidelines.
- European Association for the Study of the Liver and Asociacion Latinoamericana para el Estudio del Higado. EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol 2015; 63: 237–264.
- Castera L, Friedrich-Rust M and Loomba R. Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease. Gastroenterology 2019; 156: 1264–281.