The incidence of liver disease is steadily rising in the United States and as such, has created an increasing need for evaluation of liver disease severity and progression. Fibrosis development is a marker of progression of advanced liver disease and prognosis of many liver diseases is determined by degree and severity of fibrosis, which, if left untreated, may progress to cirrhosis. Liver biopsy has long been the standard for assessment of fibrosis; however it is expensive, invasive, and requires expert evaluation. Given these limitations, non-invasive tests (NITs) are frequently used due to their non-invasive properties, relatively cheaper cost, and repeatability, which allows for closer monitoring of changes in liver disease progression. In this paper, we review recent clinical practice guidelines to determine the differences, if any, between the recommendations regarding use of NITs.
As the incidence of liver disease continues to increase in the Unites States,1 increasing interest has turned to the evaluation of liver disease severity and progression, with a special emphasis placed on fibrosis development and progression. The development of fibrosis marks worsening of advanced chronic liver disease (ACLD) and prognostication depends on determining the degree and severity of cirrhosis. Liver biopsy has long been the standard for assessment of fibrosis, however it is expensive, invasive, can lead to serious complications and must be evaluated by experts to provide information.2,3 Given these limitations, non- invasive tests (NITs) have become the subject of increased scrutiny for their non-invasive properties, relatively cheaper cost, and repeatability- allowing for closer monitoring of changes in fibrosis and liver disease progression.4 In this paper, we review recent clinical practice guidelines to determine the differences, if any, between the recommendations regarding use of NITs.
As previously mentioned, NITs are repeatable, cheaper, and able to be performed by general practitioners. These characteristics make them more attractive as tools to be used to determine diagnosis and progression of liver fibrosis. Limitations of these tests, however, include: an inability to discriminate between stages of fibrosis, applicability across different etiologies of liver disease, and in some cases, overestimation of degree of fibrosis.4,5 All NITs can be divided into serum markers or imaging and elastography. Caution should be exercised when using these tests, as the context in which they were studied varies and may influence results.
Serum markers that function as NITs include blood-based laboratory tests and serology-based scoring systems. These include, but are not limited to: aspartate aminotransferase (AST), alanine transaminase (ALT), platelets, international normalized ratio (INR), albumin, FibroTest (FT), the NAFLD Fibrosis Score (NFS), AST to Platelet Ratio Index (APRI), and Fibrosis-4 (FIB-4) score. These patented and non-patented serum tests and scoring systems have been found to have high applicability and reproducibility, however they can be influenced by extrahepatic causes and care should be taken to ensure that there are no confounding factors.6,7 For example, the FT has been widely validated, however it relies on bilirubin measurement and in the presence of hemolysis or cholestasis, may yield falsely elevated results.6
Imaging and Elastography
Imaging and elastography modalities include methods that assess liver stiffness and anatomy of the liver and adjacent structures. Liver stiffness measurement (LSM) can be obtained from a variety of modalities such as transient elastography (TE), point shear wave elastography (pSWE), bidimensional shear wave elastography (2D-SWE), and magnetic resonance elastography (MRE). A common measurement of fibrosis is kPa and values >15 kPa strongly suggestive of ACLD. However, cutoff values vary with different disease states (Table 1). Of these modalities, TE is the most used and most widely available.5,6 LSM, however, can be falsely elevated in the presence of inflammation, venous congestion, or recent food intake and, if possible, all confounding factors should be removed for accurate results. MRE is also routinely used, but expense, limited availability, presence of metal foreign devices all limit this modality. In a few studies, MRE and computerized tomography (CT) techniques were not accurate when used to diagnose initial stages of fibrosis.4,5 Of note, MRE values are approximately one-third the value of TE and readings >5.2kPa suggest the presence of ACLD.23
Applicability in Hepatitis C and B
With the advent of direct-acting antivirals (DAAs), more patients with Hepatitis C virus has overtaken viral hepatitis as an indication for liver transplant and cause of liver related death.24 Several scores, SteatoTestTM, the fatty liver index (FLI), the hepatic steatosis index (HSI), the lipid accumulations product, and the index of NASH and nonalcoholic fatty liver disease (NAFLD)
(HCV) are achieving sustained virological response (SVR),8 which results in a decrease in fibrosis. As post- SVR liver biopsies are not routinely performed, the importance of NITs to accurately assess fibrosis regression and stage fibrosis has become a topic of increasing interest. A meta-analysis showed a 28% median decline in LSM with TE from baseline to 6-12 months after SVR compared to non-SVR
patients.9,10 Other studies with paired liver biopsies have shown that LSM decrease is greater in patients with fibrosis regression, but the degree of LSM decrease does not predict fibrosis regression.11 Overall, the consensus appears to be that NITs are poor predictors of fibrosis regression after SVR6 and further studies are needed to validate their role in the monitoring of Hepatitis C patients. Serum markers for fibrosis are not routinely used in the presence of chronic Hepatitis B (CHB) infection, as multiple variables, including immune activity and inflammatory flare affect their reliability.12,13 Fibrotest was inaccurate in identification of severe fibrosis and APRI and Fib-4 do not reflect changes in fibrosis and have limited ability to accurately diagnose fibrosis in moderately advanced disease. TE has a strong prognostic role in CHB, but the correlation between improvement in fibrosis and LSM have yet to be studied.6
Applicability in NAFLD/ NASH
The diagnosis of nonalcoholic steatohepatitis (NASH) is important, as NASH is associated with increased liver fibrosis progression and liver fat score (NAFLD-LFS) have been proposed to diagnose steatosis.14 Although many of these have been independently validated, they were all designed and validated against different modalities15 and, thus, it is difficult to compare diagnostic performance. Quantification of steatosis with controlled attenuation parameter (CAP) is a potential point-of-care technique (which can be bundled with Fibroscan) that requires further study, as results are influenced by metabolic factors and type of probe used.6 CAP also performed poorly when compared to MRI-proton density fat fraction (MRI-PDFF).4 Although, European Association for the Study of the Liver (EASL) recommendations are that TE may be used to rule out advanced fibrosis, other reviews argue that TE thresholds require further validation in more heterogenous cohorts6 and the AGA review on elastography did not give specific recommendations on the TE LSM that would diagnose cirrhosis.16 None of the available imaging modalities can consistently determine when simple steatosis transforms into NASH. Thus, liver biopsy remains the gold standard for diagnosis of NASH, though it is infrequently used due to limitations of the procedure and highrisk status of the patients.5 However, despite the differences regarding diagnostic thresholds, the majority of TE are performed on NASH/NAFLD patients and many point of care studies are ongoing due to the increased benefits of frequent evaluation of fibrosis development.5
Applicability in Alcoholic Hepatitis
Alcoholic liver disease (ALD) is the leading cause of liver related morbidity and mortality worldwide and patients with alcoholic cirrhosis are diagnosed at later stages and die earlier than patient with liver disease from other etiologies.17 With this in mind, the implementation of NITs for early disease detection and lifestyle changes including alcohol cessation, improved nutrition, and sarcopenia modification, are attractive prospects. TE has been shown to have good diagnostic accuracy in significant and advanced fibrosis and has been proven superior to serum markers.6 In many studies, cut-off values for advanced cirrhosis range from 11.5 to 25.8 kPa and EASL recommends ruling out advanced fibrosis with TE values below 8-10 kPa.6,18 Fib-4 and Forn’s (age, total cholesterol, gamma-glutamyl transferase and platelet count) can also be used to rule out advanced fibrosis in lowprevalence populations and their affordability and easy accessibility make them attractive modalities. Lastly, use of NITs is not recommended in patients with suspected alcoholic hepatitis as only 3 studies have evaluated use of NITs in this disease and they vary in definition of alcoholic hepatitis and patient cohorts.19
Applicability in Cholestatic and Autoimmune Liver Disease
As with other liver diseases, progression of fibrosis is associated with poor prognosis. In primary biliary cholangitis (PBC), liver biopsy is no longer included in work up, except in specific circumstances, and LSM with TE and point shear wave elastography (pSWE) have shown promise in predicting advanced fibrosis.21 Serum biomarkers of liver fibrosis and non-invasive scores have limited ability to accurately differentiate between stages of fibrosis and thus, should not be used for fibrosis staging.21 pSWE, MRE, and spleen length measurement by ultrasound have all shown promising results in the diagnosis of significant and advanced fibrosis,6,21,22 but further studies are needed for validation. Primary sclerosing cholangitis (PSC) is progressive in nature and patients have unpredictable fluctuations in bilirubin due to cholangitis, stones, or strictures. This characteristic complicates prognostication with classic models, such as model for end-stage liver disease (MELD) score and Child-Pugh score.4 TE is the most commonly used, validated NIT, but care should be taken to exclude biliary obstruction as obstructive cholestasis is known to falsely elevate LSM.6
In autoimmune hepatitis (AIH), TE has been found to have superior performance to serum markers, including APRI and FIB-4 and is able to detect advanced fibrosis and cirrhosis.4 Hepatic inflammation is a known confounder that falsely elevates LSM and thus, liver aminotransferases should be taken into account when assessing LSM in patient with AIH.6,20
In PBC, PSC, and AIH, TE is the best NIT in terms of diagnostic and prognostic ability, performance, and validation.6
All NITs, both serum markers and imaging elastography, are able to more accurately diagnose cirrhosis and less able to differentiate between stages of fibrosis leading to cirrhosis. The accuracy of the various tests depends on the patient population and etiology of the fibrosis. While these tests are inexpensive and generally available to most practitioners, care should be taken to ensure that they are being used in the appropriate context and that confounding factors are not affecting results.
- Scaglione S, Kliethermes S, Cao G, et al. The Epidemiology of Cirrhosis in the United States: A Population-based Study. J Clin Gastroenterol. 2015;49(8):690-696.
- Bedossa P, Dargère D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003;38(6):1449-1457.
- Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD; American Association for the Study of Liver Diseases. Liver biopsy. Hepatology. 2009;49(3):1017-1044.
- EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis – 2021 update. J Hepatol. 2021;75(3):659689.
- Castera L. Non-invasive tests for liver fibrosis in NAFLD: Creating pathways between primary healthcare and liver clinics. Liver Int. 2020;40 Suppl 1:77-81.
- Patel K, Sebastiani G. Limitations of non-invasive tests for assessment of liver fibrosis. JHEP Rep. 2020;2(2):100067. Published 2020 Jan 20.
- Fraser JR, Gibson PR. Mechanisms by which food intake elevates circulating levels of hyaluronan in humans. J Intern Med. 2005;258(5):460-466.
- EASL recommendations on treatment of hepatitis C: Final update of the series. J Hepatol. 2020;73(5):1170-1218.
- Singh S, Facciorusso A, Loomba R, Falck-Ytter YT. Magnitude and Kinetics of Decrease in Liver Stiffness After Antiviral Therapy in Patients with Chronic Hepatitis C: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018;16(1):27-38.e4.
- Persico M, Rosato V, Aglitti A, et al. Sustained virological response by direct antiviral agents in HCV leads to an early and significant improvement of liver fibrosis. Antivir Ther. 2018;23(2):129-138.
- Mauro E, Crespo G, Montironi C, et al. Portal pressure and liver stiffness measurements in the prediction of fibrosis regression after sustained virological response in recurrent hepatitis C. Hepatology. 2018;67(5):1683-1694.
- Terrault NA, Bzowej NH, Chang KM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63(1):261-283.
- Salkic, N., Jovanovic, P., Hauser, G. and Brcic, M., 2014. FibroTest/Fibrosure for Significant Liver Fibrosis and Cirrhosis in Chronic Hepatitis B: A Meta-Analysis. American Journal of
Gastroenterology, 109(6), pp.796-809.
- Stern C, Castera L. Non-invasive diagnosis of hepatic steatosis. Hepatol Int. 2017;11(1):70-78.
- Poynard T, Lassailly G, Diaz E, et al. Performance of biomarkers FibroTest, ActiTest, SteatoTest, and NashTest in patients with severe obesity: meta analysis of individual patient data. PLoS One. 2012;7(3):e30325.
- Singh S, Muir AJ, Dieterich DT, Falck-Ytter YT. American Gastroenterological Association Institute Technical Review on the Role of Elastography in Chronic Liver Diseases. Gastroenterology. 2017;152(6):1544-1577.
- Kim D, Adejumo AC, Yoo ER, et al. Trends in Mortality from Extrahepatic Complications in Patients with Chronic Liver Disease, From 2007 Through 2017. Gastroenterology. 2019;157(4):10551066.e11.
- Papatheodoridi M, Hiriart JB, Lupsor-Platon M, et al. Refining the Baveno VI elastography criteria for the definition of compensated advanced chronic liver disease. J Hepatol. 2021;74(5):1109-1116.
- Bissonnette J, Altamirano J, Devue C, et al. A prospective study of the utility of plasma biomarkers to diagnose alcoholic hepatitis. Hepatology. 2017;66(2):555-563.
- European Association for the Study of the Liver. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67(1):145-172.
- Park DW, Lee YJ, Chang W, et al. Diagnostic performance of a point shear wave elastography (pSWE) for hepatic fibrosis in patients with autoimmune liver disease. PLoS One. 2019;14(3):e0212771.
- Osman KT, Maselli DB, Idilman IS, et al. Liver Stiffness Measured by Either Magnetic Resonance or Transient Elastography Is Associated with Liver Fibrosis and Is an Independent Predictor of Outcomes Among Patients with Primary Biliary Cholangitis. J Clin Gastroenterol. 2021;55(5):449457.
- Asrani SK. Noninvasive diagnosis of liver fibrosis in adults. Clin Liver Dis (Hoboken). 2017;9(5):121-124. Published 2017 May 26. doi:10.1002/cld.632
- Shetty A, Giron F, Divatia MK, Ahmad MI, Kodali S, Victor D. Nonalcoholic Fatty Liver Disease after Liver Transplant. J Clin Transl Hepatol. 2021;9(3):428-435. doi:10.14218/JCTH.2020.00072
- Tapper EB, Lok AS. Use of Liver Imaging and Biopsy in Clinical Practice. N Engl J Med. 2017;377(8):756768. doi:10.1056/NEJMra1610570